WHO Drug Information Vol. 29, No. 1, 2015

WHO Drug Information Contents

Regulatory collaboration 22 Antibiotics EMA advice on antibiotics use in 3 The International Coalition of Medicines animals; ECDC/EFSA/EMA first joint report Regulatory Authorities (ICMRA) 23 Drug availability Canada announces requirement for reporting of drug shortages ; EU industry proposal on Norms and standards reducing manufacturing-related medicines 7 Good review practices: shortages guidelines for national and regional regulatory 24 Approvals

authorities Bupropion & naltrexone : for weight management; Liraglutide :

for weight management; Cangrelor : anti-clotting agent; Edoxaban : anti-clotting agent; Tolvaptan : for rare kidney disease

; Parathyroid hormone : to control blood calcium levels in hypoparathyroidism ; Ceftolozane &

Safety news tazobactam : for certain complicated infections; Ceftazidime & avibactam : for certain complicated

13 Restrictions infections; Finafloxacin : for outer ear infection ; Peramivir : for influenza; Lamivudine &

Metoclopramide : not for children under one year of age; Domperidone : further raltegravir; Meningococcal serogroup B

restrictions; Nitrofurantoine : revised contraindication in renal impairment; Oral diclofenac : vaccine ; Human Papillomavirus 9-valent

prescription-only in United Kingdom; Risperidone : not to be used in vascular or mixed-type dementia; Hydroxyzine : new restrictions; Codeine- Vaccine, Recombinant : for prevention of certain cancers; Sabin inactivated

containing cough and cold medicines : not for children under 12; polio vaccine (sIPV); Ceritinib : for certain lung cancers; Nivolumab :

15 Safety warnings for advanced melanoma , lung cancer; Lenvatinib : for certain progressive thyroid cancers; Palbociclib : for advanced breast cancer; Safinamide : for Parkinson’s disease;

Linagliptin : possible liver toxicity; Apixaban : interstitial lung disease; Chlorhexidine : chemical burns in premature Autologous limbal stem cells : for limbal stem cell deficiency due to burns to the eyes;

infants; Testosterone : caution about use in healthy men; Telaprevir : renal impairment; Simeprevir : leukopenia and 29 Extensions of indications

neutropenia; Mycophenolate mofetil and mycophenolic 31 Labelling changes

acid : hypogammaglobulinaemia and bronchiectasis; Vemurafenib : pancreatitis; Abiraterone : thrombocytopenia; Ziprasidone : Diabetes pen devices : for single-patient use only; Xpert® MTB/RIF test: can guide decisions on ending patient isolation;

rare but potentially fatal skin reactions; Donepezil : rhabdomyolysis and neuroleptic malignant syndrome; Ambroxol/bromhexine : rare severe skin reactions; Nitric

oxide cylinders : faulty valves ; 19 Unchanged recommendations Publications and events Analgesics in pregnancy 32 Access to treatment 19 Manufacturing quality issues Adaptive licensing pathways; Appraisal

GVK Biosciences : EMA recommends suspensions; Three Indian sites : Canada stops imports; of expensive medicines; BRICS Ministers 20 Falsified product alert tackle priority diseases; LDCs request Falsified artemether/lumefantrine in West extension of intellectual property rights Africa waiver for medicines; Medicines Patent Pool signs licensing agreements for paediatric antiretrovirals; Anti-TB drug donation agreed Regulatory news 34 Product development 21 Pre-market assessment New anti-tuberculosis medicine starts clinical Generics information-sharing pilot testing expanded; CFDA issues biosimilars 34 Disease updates

development and evaluation guideline Ebola : an unforgiving virus; Non-communicable diseases : preventable early

21 Pharmacovigilance deaths; Tuberculosis : further to go; Malaria : fragile gains; HIV: fast track targets; Neglected

EMA upgrades data systems; Canada tropical diseases : domestic investments needed; launches drug safety information web site 37 WHO matters 22 Regulatory oversight MQAS procurement guidelines now available FDA proposes new guidance on in French; Do you manufacture these APIs? compounding; CFDA strengthens good We are interested in you; New phase of practice guidance for medical devices WHO’s external quality control laboratory scheme; WHA resolutions now on official

record; WHA67.20 : Regulatory system strengthening for medical products; WHA67.21 : Access to biotherapeutic products, including similar biotherapeutic products, and ensuring their quality, safety and efficacy;

Continued

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Continued Consultation documents International Nonproprietary Names 46 The International Pharmacopoeia 46 Misoprostol 61 Recommended List No. 73 50 Clindamycin hydrochloride 53 Clindamycin hydrochloride capsules 56 Dextromethorphan hydrobromide

Abbreviations and web sites

CHMP Committee for Medicinal Products for Human Use (EMA) EMA European Medicines Agency (www.ema.europa.eu) EU European Union FDA U.S. Food and Drug Administration (www.fda.gov) Health Canada Federal department responsible for health product regulation in Canada (www.hc-sc.gc.ca) MHLW Ministry of Health, Labour and Welfare, Japan MHRA Medicines and Healthcare Products Regulatory Agency, United Kingdom (www.mhra.gov.uk) Medsafe New Zealand Medicines and Medical Devices Safety Authority (www.medsafe.govt.nz) PRAC Pharmacovigilance Risk Assessment Committee (EMA) PMDA Pharmaceutical and Medical Devices Agency, Japan (www.pmda.go.jp/english/index.htm) Swissmedic Swiss Agency for Therapeutic Products (www.swissmedic.ch) TGA Therapeutic Goods Administration, Australia (www.tga.gov.au) U.S. United States of America

Note: The online version of this issue (available at www.who.int/medicines/publications/druginformation) has direct clickable hyperlinks to the documents and web pages referenced.

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Regulatory collaboration

The International Coalition of Medicines Regulatory Authorities (ICMRA)

A new global collaboration brings together senior leaders to provide coordinated, consistent, and strategic leadership in an increasingly globalized and complex regulatory environment. The International Coalition of Medicines Regulatory Authorities (ICMRA) is a voluntary, executive level entity that provides direction for a range of areas that are common to many regulatory authorities’ missions.

The global regulatory environment ingredients, and managing the risks and Globalization directly affects the benefits requires regulators to consider protection and promotion of public international collaboration approaches to health everywhere. Medicinal products provide access to regulatory authorities’ distributed and used in domestic markets resources and the best available scientific are increasingly global commodities. The and technical expertise. The resulting manufacturing and distribution supply increase of global regulatory networks, chains are complex, multi-faceted, usually conducted at the technical/ globally integrated and may at times operational level, also calls for increased be difficult to understand or unravel. efficiency in managing the expertise and The ability of a regulator to assure resources invested in these initiatives. In the safety, quality and efficacy of a short, Medicines Regulatory Authorities medicinal product domestically requires (MRA) regulate within an extremely knowledge of and confidence in these complex domain – legally, technically, supply chains and regulatory oversight and scientifically – and recognize that the at all stages. There is also growing effectiveness of the plans and approaches complexity in medicinal products and their used to address these challenges

Authors: Professor John Skerritt, National Manager, Therapeutic Goods Administration, Australia Dr. Jaime Cesar de Moura Oliveira, President, National Health Surveillance Agency, Brazil Mr. Anil Arora, Assistant Deputy Minister, Health Products and Food Branch, Health Canada Professor Guido Rasi, former Executive Director, European Medicines Agency Dr. Andrzej Rys, Director of Health Systems and Products, Directorate General for Health and Consumers, European Commission Mr. Pat O’Mahony, Chief Executive, Health Products Regulatory Authority, Ireland Professor Luca Pani, Director General, Italian Medicines Agency Dr. Tatsuya Kondo, Chief Executive, Pharmaceuticals and Medical Devices Agency of Japan Dr. Hugo Hurts, Director, Medicines Evaluation Board, Netherlands Dr. Mimi Choong May Ling, Chief Executive Officer, Health Sciences Authority, Singapore Ms. Mandisa Hela, Registrar of Medicines, Medicines Control Council, Department of Health, South Africa Dr. Ian Hudson, Chief Executive, Medicines and Healthcare Products Regulatory Agency, United Kingdom Dr. Margaret Hamburg, Commissioner of Food and Drugs, U.S. Food and Drug Administration

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depends upon strategic-level leadership synergies to be made, and wherever and new ways of working around the possible, leverage existing efforts to globe including information-sharing which maximize global impact. Four over-arching gives room for potential synergies. objectives help to guide the ICMRA: A collective, global understanding of • to protect human health throughout the these realities has fueled international life-cycle of medicinal products; discussions over the last few years • to enable regulatory conditions which including at the World Health Assembly, facilitate improved access to and the World Health Organization’s availability of safe, efficacious and International Conference of Drug quality medicinal products. This also Regulatory Authorities (ICDRA), and includes enabling innovation and the International Summit of Heads of advancing regulatory science as it Medicines Regulatory Agencies. Leaders related to medicine research and of MRAs are harnessing this momentum development; to establish a new way of collaborating, • to promote coherent and strategic the International Coalition of Medicines multilateral cooperation among Regulatory Authorities (ICMRA). regulatory authorities, in order to strengthen mutual reliance, trust, What is the ICMRA? synergies and regulatory systems, The ICMRA is a venue for heads of and to achieve better use of collective national regulatory authorities around resources/work products and sharing of the world to enable a shared strategic best practices; and leadership to address current and • to promote the leveraging of regulatory emerging global regulatory challenges and authorities’ resources, including to better leverage resources in ways that knowledge and expertise. expand global regulatory reach (1). ICMRA has a medicines focus at this What sets the ICMRA apart from other stage, and participants are currently existing regulatory initiatives is that it working on selected joint efforts to brings together senior leaders to provide stimulate collaborative thinking and strategic, high-level advocacy and action, piloting new ways of working to leadership. ICMRA can provide direction build mutual reliance, and facilitating for a range of areas and activities that early and timely identification of emerging are common to many MRAs’ missions public health crises that intersect with and goals, identify areas for potential medical regulatory authorities (Box 1).

Box 1. Current ICMRA Working Groups 1) Governance 2) Mapping 3) Communications/Outreach 4) GMP Inspections 5) Generic Medicines 6) Rapid Sharing of Information 7) Capacity Building

4 WHO Drug Information Vol. 29, No. 1, 2015 Regulatory collaboration

Indeed, much of ICMRA’s true potential and will include regulatory authorities for is in its ability to maintain a consistent medicinal products5. and open dialogue among the heads of MRAs, enabling them to quickly connect Envisioning a framework for action on issues of mutual priority or concern. Over time, ICMRA will enable a global A good example of this coordinated architecture to support enhanced response is the September 4, 2014 communication, information-sharing and ICMRA Statement on Ebola (2). crisis response. ICMRA will also focus The ICMRA is currently operating in an on strengthening regulatory systems and interim period (2013-2015) as it builds capacity, and increasing awareness of a strong foundation for governance and and appreciation for the importance of sustainable collaboration. It is supported strong regulatory systems and functions by a Secretariat and guided by a Chair, within national, sub-regional, and global two Vice-Chairs1, and a Management contexts. Committee2. Membership3, currently ICMRA benefits are multi-faceted envisioned by a small number of current and most importantly enable MRAs members emanating from earlier heads to coalesce around regulatory issues of medicines summits4, will be voluntary of mutual priority within a 21st century environment. ICMRA benefits will be stronger confidence and collaboration among regulators, less duplication of effort 1 Health Canada’s Health Products and Food Branch (HC-HPFB) is the interim ICMRA Chair and more strategic use of human and and interim Secretariat, with Ireland’s Health financial resources. All heads of national Product Regulatory Authority and Japan’s regulatory authorities are encouraged to Ministry of Health, Labour and Welfare and remain apprised of developments within Pharmaceuticals and Medical Devices Agency as Vice-Chairs. ICMRA and engage with the ICMRA. 2 ICMRA Management Committee membership includes: Australia, Brazil, Canada, China, Potential for global synergies Europe, Ireland, Italy, Japan, the Netherlands, As ICMRA begins to determine Singapore, South Africa, the United Kingdom, and the United States. where it can best add value within an 3 Current membership in the ICMRA includes the environment of various global regulatory Heads of the regulatory authorities of: Australia efforts, it is clear that the potential for (TGA), Brazil (ANVISA), Canada (HPFB-HC), synergies are numerous. There are China (CFDA), Europe (EMA and EC), France (ANSM), Germany (PEI), Ireland (HPRA), many well-established technical and Italy (AIFA), Japan (PMDA and MHLW), Korea scientific bodies already serving unique (MFDS), Mexico (COFEPRIS), the Netherlands purposes with specific mandates, for (MEB), New Zealand (Medsafe), Nigeria example, the International Conference (NAFDAC), Singapore (HSA), South Africa (MCC), Switzerland (Swissmedic), the United on Harmonisation of Technical Kingdom (MHRA) and the United States (FDA), Requirements for Registration of with the World Health Organization (WHO) as Pharmaceuticals for Human Use (ICH) an observer. and the Pharmaceutical Inspection 4 The International Summit of Heads of Medicines Regulatory Agencies is an annual meeting that Convention and Pharmaceutical serves as an important forum for the exchange of information, views and regulatory strategies 5 Interested authorities should contact the ICMRA among the chief executives of major and like- interim Chair, Health Canada’s Health Products minded medicines regulatory agencies. and Food Branch, [email protected].

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Inspection Co-operation Scheme (PIC/S). regulatory environment. By providing Dialogue between ICMRA and these strategic and high-level oversight and organizations has already begun with guidance and early thinking, we, as the the purpose of opening and maintaining leaders of our respective regulatory ongoing communication on issues of authorities, hope to better leverage our common concern and interest. ICMRA will resources, address issues of mutual continue to connect with other initiatives, concern, and increase shared thinking and including those with a regional focus. action. We encourage all WHO Member ICMRA continues to identify areas States to increase their understanding of potential synergy on discrete topics of ICMRA and become engaged as we including: Good Manufacturing Practices move to transform the global regulatory (GMP), information-sharing and landscape. æ information-sharing platforms, Unique Facility Identifiers (UFI), generic drugs, References and capacity building. Using ICMRA as 1 International Coalition of Medicines a venue to convene MRAs on topics Regulatory Authorities (ICMRA). Fact Sheet. of mutual priority can yield significant September 2014. benefits. 2 Statement on international regulatory In sum, the ICMRA is a new governance cooperation regarding Ebola [News release]. Health Canada, 4 September 2014. and leadership model in the global

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Norms and standards

Good review practices: guidelines for national and regional regulatory authorities *

This is a summary of a guideline on good regulatory review practices developed through an inter-organizational collaboration. It is the first set of guidelines of its kind globally and addresses an important gap identified at the 2012 International Conference of Drug Regulatory Authorities (ICDRA). The full text as adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations in October 2014 will be published as an annex to the Expert Committee’s report; the draft published for comment prior to the Committee’s meeting is available on the WHO web site (1).

The benefits of good review through the exchange of review reports practices and better mutual understanding among Regulatory authorities (RAs) are RAs. This is a significant benefit as the increasingly seeking ways to improve use of reviews and decisions reached their performance and ensure the quality by other RAs is expected to become of their regulatory systems. Medical increasingly important in achieving review product review is that part of regulatory efficiencies in the face of pressures on work that forms the scientific foundation resources. for regulatory decisions on marketing authorizations. It requires a highly Guideline development complex, multidisciplinary assessment In June 2013 the Asia-Pacific Economic of product data to ensure that products Cooperation (APEC) Regulatory submitted for regulatory approval meet Harmonization Steering Committee adequate scientific and evidentiary (RHSC) convened an expert working standards for safety, efficacy and quality. group with WHO representation to develop Implementation of good review a draft good review practices document, practices helps RAs to achieve timely intended to cover both medicines and reviews with high quality outcomes, with medical devices, for submission to WHO a significant impact on public health, for in early 2014. WHO risk management example in terms of patients’ access to principles (2) and the results of an APEC important medical products, and costs to survey (3) were among the key references both government and applicants. used in developing this text. Good review practice also facilitates The draft document was accepted for progress towards regulatory convergence parallel public consultation processes

* Asia-Pacific Economic Cooperation (APEC) Regulatory Harmonization Steering Committee (RHSC) good review practices (GRevP) with the participation of Working Group Members representing the regulatory authorities (RAs) from the economies of Australia, Canada, Taipei (China), Japan, Republic of Korea, Saudi Arabia, Singapore, United States of America; and representatives of the Centre for Innovation in Regulatory Science (CIRS); and the Food and Drug Administration Alumni Association International (FDAAA).

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for both the WHO Expert Committee of GRevPs is to help achieve timeliness, on Specifications for Pharmaceutical predictability, consistency, transparency, Preparations and the WHO Expert clarity, efficiency and high quality in both Committee on Biological Standardization. the content and management of reviews. This led to a guidance text on good review This is done through the development practices for regulatory authorities being of review tools (for example, standard adopted by the WHO Expert Committee operating procedures (SOPs) and on Specifications for Pharmaceutical templates) and reviewer learning activities Preparations at its forty-ninth meeting, (for example, training courses, mentoring, held on 13–17 October 2014 in Geneva. orientation packages and discussion sessions). To promote continuous Objective and scope improvement, all aspects of GRevPs The objective of the document is to should be continuously evaluated and provide high-level guidance on the updated.” principles and processes of good review The document proposes ten key practice for use across a range of RA principles of a good review as a general maturities. It is not intended to provide guide for RAs (see Box 1). detailed instruction on how to conduct a scientific review. Rather, it is envisioned Managing the review as one building block in a set of tools and The principles of project management and is sufficiently expandable to accommodate quality management are critical to achieve additional annexes or ancillary documents efficient and effective review processes. in the future. The principles and elements Project management refers to the described in this document can be planning, organizing and resourcing adapted to meet the continuous needs for necessary to achieve a complete and improvement of a diverse range of RAs. high-quality review of an application Although the document was written within a specified time frame. RAs should to provide guidance on pharmaceutical identify the most suitable techniques products and biologicals and higher-risk enabling them to monitor the progress of medical devices used in humans, the one or many applications under review at concepts may be applied to other types of any one time, to help in decision-making medical products. Similarly, the concepts on how to balance workload against could also be applied to the entire product resources, and to enable monitoring and/ life cycle from investigational testing or its interpretation by the relevant people. to new product applications, updates Quality management – the coordinated or variations to existing marketing activities that direct and control an authorizations and maintenance of the organization with regard to quality – product. ensures that GRevPs are in place, regularly monitored and subject to What is good review practice? continuous improvement. The quality cycle The guidelines define good review is made up of four key components: practices (GRevPs) as “documented best • say what you do, practices for any aspect related to the • do what you say, process, format, content and management • prove it, and of a medical product review. The objective • improve it.

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Box 1: Ten key principles of a good review

Balanced nonclinical, clinical, chemistry/biocompatibility, A good review is objective and unbiased. manufacturing and risk management plan. It includes timely communication Considers context and consultation with applicants, internal A good review considers the data and the stakeholders and, as needed, with external conclusions of the applicant in the context stakeholders who have expertise relevant of the proposed conditions of use and to the various aspects of the application. storage, and may include perspectives from patients, health-care professionals Utilizes critical analyses and other RAs’ analyses and decisions. A good review assesses the scientific integrity, relevance and completeness of the data and Evidence-based proposed labelling, as well as the interpretation A good review is evidence-based and reflects thereof, presented in the application. both the scientific and regulatory state of the art. It integrates legislative, regulatory and Thorough policy frameworks with emerging science. A good review reflects adequate follow- through of all the issues by the reviewers. Identifies signals A good review comprehensively highlights Well-documented potential areas of concern identified by A good review provides a well-written and the applicant and the reviewers. thorough report of the evidence-based findings and conclusions provided by the Investigates and solves problems applicant in the dossier, and the reviewers’ A good review provides both the applicant’s and assessment of the conclusions and rationale the reviewers’ in-depth analyses and findings for reaching a decision. It contains clear, of key scientific data and uses problem-solving, succinct recommendations that can stand regulatory flexibility, risk-based analyses and up to scrutiny by all the parties involved synthesis skills to devise and recommend and could be leveraged by others. solutions and alternatives where needed. Well-managed Makes linkages A good review applies project and quality A good review provides integrated analysis management processes, including clearly across all aspects of the application: preclinical, defined steps with specific activities and targets.

This cycle ensures that GRevPs are not and facilitate staff training. SOPs can be merely theoretical guidelines (“say what complemented by companion documents you do”) but become embedded in the such as guidelines, templates and daily practice of an agency (“do what you checklists, and can be designed both say”). Quality management can also help for internal use and to guide applicants an agency review its practice (“prove it”) seeking marketing authorization. and evolve where necessary, either in SOPs will require updating in line with response to evolving regulatory science evolving scientific progress, international or through the adoption of new review harmonization of guidelines, changes processes and procedures (“improve it”). in review strategy, available resources, Standard operating procedures increased volume of applications, (SOPs) enable RAs to outline workflow collaborative work-sharing, and national processes, handle and review product laws and regulations, among others. applications in a consistent manner,

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Review process stages medical or scientific organizations) to The review process has two key stages: make use of valuable expertise while firstly a validation stage (also called ensuring confidentiality and absence of screening) to identify missing information conflict of interest; and in the application, ensuring that time • with the public, to foster awareness, and review resources are only spent on understanding of and confidence in the applications that have enough data to RA, and to obtain input on proposed allow critical analysis, signal identification regulations and/or specific applications. and regulatory decision-making, and secondly the actual scientific review, Review personnel discussed in more detail below. Applicants The quality, timeliness and success of should be made clearly aware of the RA’s medical product reviews are dependent expectations at both stages. on a sufficient number of competent reviewers. The guideline outlines the Communications expertise, competencies and training Good communication is critical and has required to deal with the various aspects many advantages for RAs, applicants and of managing and conducting reviews. the public. It can improve the efficiency of Reviewers may be RA staff, external the development and review processes experts or both. Reviewers should be and thus ultimately speed up patient free of actual or perceived conflicts access to good quality medical products. of interests, meaning that the review Communications can take many active decision or recommendation is not likely to forms, from providing information on RAs’ be influenced by personal, family, financial websites to engaging with the international or professional motives, including those community on RA projects. The guidelines of employers when an external expert is outline best practices for communication also a consultant to the regulated industry. and their benefits at various levels: Review staff should follow sound ethical • within RAs, for effective coordination of practices. organizational units carrying out different Reviewers should keep their scientific pre- and postmarketing functions (for expertise up to date. The guidelines example pharmacovigilance, inspection propose various approaches for and others); professional development of review staff, • between RAs, enabling peer making use of opportunities both within collaboration and cooperation, and outside the RA. whereby interagency communications can also facilitate greater regulatory Critical thinking and good convergence; judgement • with applicants, to provide insight Critical thinking is important for reviewers into the RA’s current thinking and to make decisions that are reproducible expectations, enabling a mutual better and clearly understood by others. understanding and therefore better Reviewers should have the ability quality applications; to critically appraise the information • with external experts (for example presented in an application and not from academic institutions, industry just accept it as presented. This skill associations, patient organizations and can be strengthened by learning from

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senior reviewers and through discussion high background incidence of the same among reviewers and external experts on organ disease, use of a new end point application-specific issues. for regulatory approval that may not be Good judgement is required for a direct measure of clinical benefit, or reviewers to come to balanced decisions. use of conditions for stability testing that This involves focusing on the important are not appropriate for the RA’s regional issues in the application and adopting climate). Early identification of complex those regulatory approaches that or precedent-setting issues or areas will maximize public health benefits of high uncertainty in the application while minimizing adverse, unintended can lead to faster and more efficient consequences. resolution, based on an early review of Regulatory decision-making should be the most relevant available data. based on the best current science, in the context of each country’s public health Conducting the review needs and its medical care system. The The way in which a review is conducted scientific rationale for decision-making, will depend on available resources. While including all information used and any a multidisciplinary team will provide dissenting, evidence-based views, should broader expertise, in some cases an be documented to ensure the integrity application may be assigned to a single of the review process. Decision-making reviewer, seeking input from external by an RA should be independent of experts and/or considering the information influences beyond public health. and decisions of other RAs as needed. The review should be evidence-based, Review strategy taking into account national laws and For each specific application, a review regulations, regional and international strategy – i.e. an approach or plan of guidelines and, where applicable, action – should be defined and followed monographs and standards. The reviewer by the reviewer or review team to ensure should determine the information a sound review process. The strategy necessary to approve the product, and employed may be shaped by: consider what further studies (if any) can • the public health priority of the medical be left for the post-approval stage without product submitted for review; compromising safety. • other RAs’ action on the product, taking The model adopted for review may into account any product differences (for allow for questions to be asked during example formulation or final container the review to supplement or clarify the presentation) and any differences in the information supplied, until the reviewer proposed indications or conditions of is satisfied that enough data have been use in the local population; provided for a conclusion to be reached. • specific intrinsic and extrinsic factors In other models, the review is completed that are clinically relevant to the on the basis of the information submitted, population served by the RA; and a list of questions is then sent to the • major scientific questions on product applicant with a time-limit for response, safety, efficacy or quality (examples: and one further round of assessment identification of possible cases of organ of the responses takes place before a toxicity in a patient population with a decision is made.

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The following internal processes may review report, and the final decision help ensure an efficient, consistent and should be conveyed to the applicant. If an effective review process: RA decides not to grant authorization, a • periodic meetings to allow consideration statement of reasons should be provided of the views of different reviewers; which details the documents, information • peer review, in the context of a and regulatory requirements taken into co-rapporteur, or a team meeting; account in reaching the decision. An • an internal panel review; appeal mechanism should be provided • an external panel review; and giving applicants an opportunity to present • the involvement of senior management. their case to an independent arbiter. Some RAs may offer to hold a post- Quantifying risks and benefits action discussion with the applicant to help The review strategy should enable the improve the quality of future applications. reviewer or review team to understand Lastly the RA may also implement and describe the benefit–risk profile of the mechanisms for public communication of medical product, given its indication and review outcomes and related information, context of use. Benefits and risks can be increasing the transparency of its quantified or qualitatively characterized, regulatory actions. æ and the levels of certainty surrounding the benefits and risks should be stated. The References review should address generalizability 1 Full text of the guideline summarized of the data, the clinical significance of in this article: Good review practices: the findings and what (if any) additional guidelines for national and regional information may be needed to clarify regulatory authorities. In: WHO Expert Committee on Specifications for benefits and risks. Pharmaceutical Preparations. Forty-ninth The acceptability of benefits and risks report. Geneva, World Health Organization. will depend on public health priorities, Technical Report Series No. 992, 2015, available alternative therapies, the size Annex 9 (in preparation). and certainty of the treatment effect versus Draft published for comment: Good review practices: guidelines for regulatory that of the adverse reactions, and possible authorities. Working document QAS/14.576 risk mitigation or benefit enhancement Rev.1. August 2014. measures (for example responder 2 Guidelines on quality risk management. In: analyses to identify a population more WHO Expert Committee on Specifications likely to experience benefits). The benefit– for Pharmaceutical Preparations. Forty- risk profile may vary depending on intrinsic seventh report. Geneva, World Health and extrinsic factors that may differ Organization. Technical Report Series, among countries and regions. Moreover, No. 981, 2013, Annex 2. judgement may vary within and among 3 Liu L-L et al. Characterizing Good Review Practices: A Survey Report Among RAs. Evidence-based and public health- Agencies of APEC Member Economies. focused decision-making principles may Therapeutic Innovation & Regulatory serve to mitigate some of the variation. Science, November 2013; 47(6): 678- 683. First published on July 19, 2013. Review report doi:10.1177/2168479013494394. The findings and conclusions of the review must be described in a well-documented

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Safety news

Restrictions manufacturer has decided to reduce the maximum recommended dose from 80 mg Metoclopramide: not for children to 40 mg daily. (2) under one year of age Canada – The marketing authorization Canada – Health professionals have been holder, in consultation with Health informed of additional safety information Canada, has warned that neurological about some cardiac risks associated adverse events can occur in children with domperidone. The medicine is now receiving metoclopramide within the daily contraindicated in Canada in patients with recommended dosage of 0.5 mg/kg. prolonged of cardiac conduction intervals, Metoclopramide is now contraindicated significant electrolyte disturbances, in children less than one year of age in cardiac disease or liver impairment, and Canada, as a Health Canada review those receiving QT-prolonging drugs or has shown that they are at greater risk potent CYP3A4 inhibitors. Domperidone of abnormal involuntary movements should be used at the lowest effective (extrapyramidal symptoms). In children dose up to a maximum recommended over one year metoclopramide should only daily dose of 30 mg and for the shortest be used if the anticipated benefits clearly possible duration. outweigh the potential risks. ►►(1) Drug Safety Update volume 8 issue 2, ►►Health Canada Advisory, 5 January 2015. September 2014: S1. (2) Medsafe Safety information, 22 December 2014. Domperidone: further restrictions (3) Health Canada Advisory, 20 January United Kingdom – Further to a 2015. recommendation by the European Medicines Agency (EMA) to restrict the use of domperidone to the management Nitrofurantoine: revised of nausea and vomiting due to adverse contraindication in renal effects on the heart (see WHO Drug impairment Information Vol. 28, No. 2), domperidone- United Kingdom – The Medicines and containing medicines have been restricted Healthcare Products Regulatory Agency in the United Kingdom for supply (MHRA) has recommended to lower on prescription only with effect from the estimated glomerular filtration rate 4 September 2014. (1) (eGFR) below which nitrofurantoin is New Zealand – A Medsafe review has contraindicated. Its use should now be concluded that domperidone-containing allowed in patients with an eGFR of 45 ml/ medicines have a small increased risk min/1.73m2 or more (previously: 60 ml/ of adverse heart effects, which may be min/1.73m2). A short course (3 to 7 days) higher in patients over 60 years or at may be used with caution in certain total daily doses of more than 30 mg. The patients with an eGFR of 30–44 ml/

13 Safety news WHO Drug Information Vol. 29, No. 1, 2015

min/1.73m2 to treat lower urinary tract Risperidone: not to be used in infection with suspected or proven vascular or mixed-type dementia multidrug-resistant pathogens. Canada – Health Canada has The efficacy of nitrofurantoin in restricted the indication for risperidone treating and preventing urinary tract (Risperdal®) in dementia to the short-term infections depends on its renal secretion symptomatic management of aggression into the urinary tract. The revised or psychotic symptoms in patients with recommendations consider the fact severe dementia of the Alzheimer type that lower urinary tract pathogens are unresponsive to non-pharmacological increasingly resistant to standard therapy approaches and when there is a risk of (trimethoprim and amoxicillin), and that harm to self or others. The indication no the widespread use of alternative broad- longer includes the treatment of other spectrum antibiotics (cephalosporins and types of dementia. fluoroquinolones) is associated with the The recommendation is based risk of Clostridium difficile colitis. on available safety information on ►►Drug Safety Update volume 8 issue 2, antipsychotic drugs, indicating a higher September 2014: A3. risk of cerebrovascular adverse events in patients with mixed and vascular dementia compared to those with dementia of the Oral diclofenac: prescription-only Alzheimer type. in United Kingdom ►►Health Canada Advisory, 18 February 2015. United Kingdom – Diclofenac 12.5mg and 25mg tablets, formerly available over the counter, have been re-classified as a Hydroxyzine: new restrictions prescription-only medicines in the United European Union – The EMA’s Kingdom with effect from 15 January Pharmacovigilance Risk Assessment 2015. Committee (PRAC) has completed A 2013 Europe-wide review had found a review of medicines containing the that systemic diclofenac is associated antihistamine hydroxyzine. These are with a small increased risk of arterial available in most EU countries for various thromboembolic events, similar to indications such as treatment of anxiety that of COX-2 inhibitors. In the United disorders and sleep disorders, relief Kingdom the Commission on Human of itching caused by urticaria, and as Medicines (CHM) has reconsidered premedication before surgery. available evidence and has concluded The PRAC considered that hydroxyzine that the risk of these side effects cannot is associated with a small but definite risk be ruled out even when the medicine is of QT interval prolongation and torsade de taken for a short time or at a lower dose. pointes, which can lead to abnormal heart The Commission therefore advised that rhythms and cardiac arrest. patients should have a medical review To minimize the risk the Committee has before taking oral diclofenac to make sure recommended a number of restrictions. it is suitable for them. Use is not recommended in the elderly. ►►MHRA Press release, 14 January 2015. Duration and dosage should be reduced to minimum effective levels. The maximum daily dose should be no more than 100 mg

14 WHO Drug Information Vol. 29, No. 1, 2015 Safety news

in adults (50 mg in the elderly if use elevations, and should consider stopping cannot be avoided), and 2 mg per kg body linagliptin in case of abnormalities. weight in children up to 40 kg in weight. ►►PMDA Summary of investigation results Use must be avoided in patients who and Revisions of Precautions for linagliptin, have risk factors for arrhythmias or are 9 January 2015. taking other medicines associated with QT See also: Kutoh E. Probable linagliptin- prolongation; care is needed in patients induced liver toxicity: A case report. Diabetes Metab. 2014 Feb;40(1):82-4. doi: taking medicines that slow the heart rate 10.1016/j.diabet.2013.09.009. or decrease blood potassium levels. ►►EMA Press release, 13 February 2015. Apixaban: interstitial lung disease Japan – The MHLW/PMDA has Codeine-containing cough and recommended to revise the product cold medicines: not for children information for the anti-coagulant under 12; apixaban (Eliquis®) following reported New Zealand – Medsafe’s Medicines cases of haemorrhage and bloody sputum Adverse Reactions Committee has suggestive of interstitial lung disease, recommended to restrict the use of including suspected interstitial pneumonia all codeine-containing cough and in some cases. cold medicines for children, including ►►PMDA Summary of investigation results, prescription-only-medicines, to children 17 February 2015. aged 12 years and over. An EMA review of these medicines started in April 2014 following concerns of morphine toxicity Chlorhexidine: chemical burns in and respiratory depression. premature infants ►►Minutes of the 160th Medicines Adverse United Kingdom – The MHRA has Reactions Committee Meeting, 4 December warned health professionals that alcohol- 2014. based and aqueous chlorhexidine solutions used for skin antisepsis prior to invasive procedures can cause chemical Safety warnings burns in neonates. This risk appears to be higher in preterm infants, especially those Linagliptin: possible liver toxicity born before 32 weeks of gestation, and Japan – Following reports of hepatic within the first two weeks of life. dysfunction in patients treated with Health professionals should remove linagliptin in Japan, the Ministry of any soaked materials before proceeding Health, Labour and Welfare (MHLW) with the intervention. They should not and the Pharmaceuticals and Medical use excessive quantities of chlorhexidine Devices Agency (PMDA) of Japan have and should not allow the solution to pool recommended to update the product in skin folds or under the patient or to information to include this risk. drip on any material in direct contact with Health professionals should monitor the patient. Before applying occlusive patients treated with linagliptin for signs of dressings, care must be taken to remove liver dysfunction, including liver enzyme any excess chlorhexidine. ►►Drug Safety Update. Feb 2015; 8 (7): 4.

15 Safety news WHO Drug Information Vol. 29, No. 1, 2015

Testosterone: caution about use in initial dose in patients who are at risk of healthy men renal impairment. United States of America – The The recommendation is based on U.S. FDA has cautioned about using an interim analysis of post-marketing testosterone products to treat low surveillance survey data indicating that testosterone levels due to aging. The a full initial dose, higher age, increased Agency requires labelling changes baseline creatinine, and diabetes mellitus to clarify the approved indications or hypertension as comorbidities are risk of testosterone and to inform health factors for serious renal impairment in professionals and patients of possible patients treated with telaprevir. increased risks of heart attack and stroke ►►PMDA Summary of investigation results, associated with the use of these products. 17 February 2015. Prescription testosterone products are approved in the U.S. only to treat low testosterone levels caused by Simeprevir: leukopenia and certain medical conditions. The FDA neutropenia has become aware that testosterone Japan – Following reports of adverse is being used extensively in attempts events suggestive of leukopenia and/ to relieve symptoms in men who have or neutropenia in patients treated with low testosterone levels for no apparent combination therapy of simeprevir sodium, reason other than aging. The Agency peginterferon and ribavirin in Japan, the cautions that the benefit and safety MHLW/PMDA has recommended to revise of these medications have not been the package insert for simeprevir. Health established in this patient group – even professionals should monitor patients if a man’s symptoms seem related to low for leukopenia and/or neutropenia, and testosterone – and that some studies in should consider stopping simeprevir in aging men treated with testosterone have case of severe abnormalities. reported an increased risk of heart attack, ►►PMDA Summary of investigation results stroke or death. (1) and Revision of Precautions for simeprevir Warnings about the possible cardiac sodium, 9 January 2015. risks associated with testosterone have also been communicated recently by the EMA and New Zealand’s Medsafe (2). Mycophenolate mofetil ►►(1) FDA Drug safety communication, 3 and mycophenolic acid: March 2015. hypogammaglobulinaemia and (2) WHO Drug Information,Vol. 28, No. 4, bronchiectasis 2014: 448. United Kingdom – In accordance with a review and recommendations by the EMA’s Pharmacovigilance Risk Telaprevir: renal impairment Assessment Committee (PRAC), Japan – The MHLW/PMDA has the marketing authorization holder of recommended a revision of the product mycophenolate mofetil (CellCept®) information for telaprevir, used to treat in the United Kingdom has informed chronic hepatitis C infection, advising health professionals of the risk of health professionals to consider a reduced hypogammaglobulinaemia and the

16 WHO Drug Information Vol. 29, No. 1, 2015 Safety news

risk of bronchiectasis associated with information for abiraterone tablets the medicine. Mycophenolate mofetil (Zytiga®), used to treat castration- is registered in the United Kingdom to resistant prostate cancer, to warn prevent acute transplant rejection and is health professionals of the risk of used off-label in a number of specialties. thrombocytopenia (1). A safety signal was Serum immunoglobulin levels should identified in 2013 from Individual Case be measured in patients developing Safety Reports (ICSRs) available in the recurrent infections and clinical action WHO Global ICSR database, VigiBase™, taken as needed, taking into account the warranting further investigation (2). potent cytostatic effects of the drug on B- The product information in Japan and T-lymphocytes. In case of persistent was updated at the same time to respiratory symptoms bronchiectasis or include the risks of hypokalaemia and pulmonary fibrosis should be suspected. rhabdomyolysis, two adverse events ►►Drug Safety Update volume 8 issue 6, already reflected in FDA- and EMA- January 2014: 3. approved product information. ►►(1) PMDA Revisions of precautions, 2 February 2015. Vemurafenib: pancreatitis (2) Herrera Comoglio R. Abiraterone and Canada – A new warning about the risk thrombocytopenia. WHO Pharmaceuticals of pancreatitis has been added to the Newsletter 4, 2013: 20-25. Canadian prescribing information for vemurafenib (Zelboraf®). Vemurafenib is used to treat unresectable or metastatic Ziprasidone: rare but potentially melanoma with a BRAF mutation in adult fatal skin reactions patients. United States of America – The FDA Cases of drug-induced pancreatitis have has warned that the antipsychotic drug been reported with the use of vemurafenib ziprasidone (Geodon® and generics) is both in Canada and elsewhere. The associated with a rare but serious skin reactions generally occurred during reaction known as Drug Reaction with the first two weeks of treatment. Health Eosinophilia and Systemic Symptoms professionals should suspect pancreatitis (DRESS), which can progress to affect in patients taking vemurafenib and other parts of the body and can be fatal. presenting with unexplained abdominal A warning about this risk has been pain. If vemurafenib is re-started after an added to the label of the capsule, oral episode of pancreatitis, patients should be suspension and injection formulations of closely monitored and a dose modification this drug. Patients who have a fever with should be considered. a rash and/or swollen lymph nodes should ►►Health Canada Advisory, 12 February 2015. seek urgent medical care. Health care professionals should immediately stop treatment with ziprasidone if DRESS is Abiraterone: thrombocytopenia suspected. Japan – The MHLW/PMDA has ►►FDA Drug safety communication, recommended to revise the product 11 December 2014.

17 Safety news WHO Drug Information Vol. 29, No. 1, 2015

Donepezil: rhabdomyolysis and erythema multiforme and Stevens- neuroleptic malignant syndrome Johnson syndrome, to the product Canada – Health Canada has information for ambroxol- and bromhexine- communicated new warnings for containing medicines, which are widely donepezil, used in the treatment of used in the EU as expectorants. Alzheimer’s disease. This medicine The recommendations originated is associated with a risk of two rare from the EMA’s Pharmacovigilance Risk but potentially serious conditions: Assessment Committee (PRAC), whose rhabdomyolysis, a rare condition involving review of the two medicines confirmed the breakdown of muscle tissue, and the known risk of allergic reactions and neuroleptic malignant syndrome (NMS), identified a small risk of SCARs. a very rare life-threatening disorder ►►EMA Press release, 27 February 2015. characterized by a chemical imbalance that affects the nervous, muscular and cardiovascular systems. Nitric oxide cylinders: faulty valves ; Before prescribing donepezil health European Union – The manufacturer, professionals should assess patients in cooperation with EMA and national for risk factors for rhabdomyolysis such regulatory authorities, has informed health as: muscular disorders, uncontrolled professionals in EU Member States that hypothyroidism, liver or kidney damage, a defect might cause the valves in some and concomitant use of other medicines nitric oxide (INOmax®) cylinders to close that can cause rhabdomyolysis such as while in use and before the cylinder is statins, antipsychotics, and certain types emptied. This abruptly stops gas delivery of antidepressants. Donepezil therapy earlier than expected. Life-threatening should be stopped if blood tests show high rebound effects can occur if the cylinder is levels of creatine phosphokinase (CPK), not changed immediately. and/or if NMS and/or rhabdomyolysis is The defect applies to 400 ppm and diagnosed. 800 ppm cylinders of both the 2 L and ►►Health Canada Advisory, 21 January 2015. 10 L pack sizes. To minimize the adverse reactions health professionals should always have a full spare cylinder loaded Ambroxol/bromhexine: rare severe onto the delivery device, always use skin reactions devices with pressure sensor monitors European Union – The Co-ordination and gas monitor alarms, and when Group for Mutual Recognition and switching cylinders purge the regulator Decentralised Procedures – Human of the second cylinder before connecting

(CMDh) – a regulatory body representing it to the device to prevent excessive NO2 EU Member States – has endorsed formation. For all patient transfers, even recommendations to add information short transfers, back-up cylinders should about a small risk of severe allergic be kept available. reactions, including severe cutaneous ►►MHRA. Drug Safety Update volume 8 issue adverse reactions (SCARs) such as 7, February 2015: 2.

18 WHO Drug Information Vol. 29, No. 1, 2015 Safety news

Unchanged recommendations The CHMP has identified those medicines for which insufficient clinical Analgesics in pregnancy data are available from other sites, and United States of America – In response has recommended their suspension to reports questioning the safety of pain unless a national authority considers that medicines during pregnancy, the FDA a medicine is of critical importance to has reviewed three types of potential meet patients’ needs in the specific EU risks: 1) risk of miscarriage following Member State. In that case, the marketing use of prescription non-steroidal anti- authorization holder is given 12 months to inflammatory drugs (NSAIDs) in the first submit additional data. (1) half of pregnancy, 2) risk of birth defects Some marketing authorisation holders following administration of opioids during have requested a re-examination. (2) the first trimester of pregnancy, and 3) risk of attention deficit hyperactivity disorder Switzerland – The Swiss Agency for in the infant following paracetamol use at Therapeutic Products (Swissmedic) any time of pregnancy. has identified three products that are The studies reviewed did not provide authorized for export from Switzerland sufficiently consistent data to allow reliable on the basis of clinical trials by GVK conclusions. FDA recommendations on Biosciences in Hyderabad (India). the use of analgesics during pregnancy Swissmedic will now review these will remain unchanged. authorizations in detail. (3) ►►FDA Drug safety communication, 9 January 2015. WHO – Two products prequalified by WHO for purchase by UN agencies have been withdrawn voluntarily by the Manufacturing quality issues company from the WHO prequalification list; new data are under assessment for a GVK Biosciences: EMA third prequalified product.(4) recommends suspensions European Union – The EMA’s Committee ►►(1) EMA Press release, 23 January 2015. for Medicinal Products for Human Use (CHMP) has recommended to suspend (2) EMA News, 27 February 2015. some 700 pharmaceutical forms and (3) Swissmedic Announcement, 6 February 2015. strengths of medicines authorized in EU Member States based primarily on clinical (4) PQP Information note, 16 January 2015. studies conducted at GVK Biosciences in Hyderabad, India. An inspection by the French medicines Three Indian sites: Canada stops agency ANSM had raised concerns about imports ; prolonged and systematic non-compliance Canada – Health Canada has requested with good clinical practice at GVK’s Canadian importers to stop the Hyderabad site. This does not mean that importation and distribution of products the medicines concerned are necessarily from a number of manufacturing sites in unsafe for patients, but that reliable data India due to data integrity concerns. Action are needed to prove their bioequivalence. taken in December 2014 applied to active

19 Safety news WHO Drug Information Vol. 29, No. 1, 2015

pharmaceutical ingredients (APIs) from IPCA Laboratories facility (see WHO Drug Dr. Reddy’s Laboratories in Srikakulam Information, Vol. 28, No. 4). and to finished drug products from The import stop is a precautionary IPCA Laboratories in Pithampur; action measure. Health Canada has not taken in January 2015 applied to health identified a risk to health, nor has it products made with APIs from Sri Krishna requested a recall of any of the products. Pharmaceuticals Ltd. in Hyderabad, India. ►►Health Canada Advisory, 23 December In September and October 2014 Health 2014. Canada had already imposed import Health Canada Advisory, 6 January 2015. restrictions on pharmaceutical products from some Indian sites, including another æ

Falsified product alert

Falsified artemether/lumefantrine in West Africa Following notification from the Global Fund to Fight AIDS, Tuberculosis and Malaria, WHO has received confirmation that falsified packs of artemether/lumefantrine antimalarial tablets have been found in West Africa. The falsified productscontain none of the correct active pharmaceutical ingredients. The packs bear the following markings:

• Falsified product purchased in a street market in Abidjan, Côte d’Ivoire: Batch number: DYI402542 on the box (secondary packaging) DYI402201 on the blister foil (primary packaging) Manufacturing date: 07/2013, Expiry date: 06/2016

• Falsified product found in a drug store in Lomé, Togo during an INTERPOL operation: Batch number: DYI402541 on the outer bulk pack (tertiary packaging) DYI402542 on the box (secondary packaging) DYI402201 on the blister foil (primary packaging) Manufacturing date: 07/2013, Expiry date: 07/2016

All the above packaging levels bear the ACTm green leaf logo of the Affordable Medicines Facility malaria programme. The writing on the packaging is in English. WHO is calling for increased vigilance for these specific batches of this product. To report any information concerning these batches, or to report other incidents concerning falsified medicines, please contact [email protected]. ►►WHO Medical Product Alert No. 1/2015, February 2015. (Includes photographs)

20 WHO Drug Information Vol. 29, No. 1, 2015

Regulatory news

Pre-market assessment development of the biomedicine industry, the China Food and Drug Administration Generics information-sharing pilot (CFDA) has issued the Technical expanded Guideline for Development and Evaluation European Union – The EMA is ready of Biosimilars (interim), and has specified to share its assessments of applications relevant requirements on the application also for generic medicines that fall under procedure, registration classification, and the EMA’s centralized procedure. The application documents of biosimilars. information-sharing initiative started in ►►CFDA Press release, 5 March 2015. July 2014 using the EU decentralized procedure as a model. This initiative, under which EU Pharmacovigilance assessment information is shared in real time with collaborating regulatory EMA upgrades data systems agencies outside the European Union European Union – The EMA has (EU), is part of the International Generic completed two separate steps to develop Drug Regulators Pilot (IGDRP). It brings its reporting systems in accordance with together 14 regulatory authorities as the EU pharmacovigilance legislation. well as the European Directorate for Firstly, the Agency has published a the Quality of Medicines & Healthcare guide to support the implementation of (EDQM) and WHO as observers. a new international ISO standard for The first phase of the pilot project reporting of suspected side effects of will involve the EU, Australia, Canada, medicines in Individual Case Safety Chinese Taipei and Switzerland. Ten Reports (ICSRs). The standard will applications for generic medicines will be enhance the European EudraVigilance selected initially. Further information has adverse events database. It will bring been published on the EMA website. a globally harmonized format for case ►►EMA news, 19 January 2015. reports collected by pharmaceutical More about IGDRP: The International companies and regulatory authorities, Generic Drug Regulators Pilot. WHO Drug better quality of data to detect and Information. 28(1); 2014:3-10. address medicines safety issues, and stronger personal data protection. The use of the new standard will take effect on CFDA issues biosimilars 1 July 2016. (1) development and evaluation Secondly, the EMA has launched a guideline centralized electronic repository for China – In order to guide and standardize periodic safety update reports (PSURs) the development and evaluation of and their assessment reports. The biosimilars and promote the sound platform will make it easier for regulators

21 Regulatory news WHO Drug Information Vol. 29, No. 1, 2015

to access the information and for industry a draft Memorandum of Understanding to submit their PSURs electronically. (2) between the FDA and the states. ►►(1) EMA News, 21 January 2015. The draft documents are applicable to (2) EMA News, 26 January 2015. pharmacies, federal facilities, outsourcing facilities and physicians. The new category of outsourcing facilities was Canada launches drug safety created in 2013 in response to a fungal information web site meningitis outbreak that was linked to Canada – The Government of Canada contaminated compounded drug products. has launched a new online tool for drug ►►FDA News release, 13 February 2015. safety information. The Drug and Health Product Register provides consumers with centralized access to information CFDA strengthens good practice on prescription drugs, including their guidance for medical devices indications, safety warnings and China – The China Food and Drug precautions, common side effects, and Administration (CFDA) has issued two adverse reactions that have been reported regulatory good practice documents to Health Canada. for medical devices: the revised Good Currently in its pilot phase, the Drug Manufacturing Practice for Medical and Health Product Register covers the Devices, effective from 1 March 2015 top 100 prescribed products based on (1), and the country’s first Good Supply IMS-reported Canadian sales for 2013, Practices for Medical Devices, effective together with an additional 250 products from 12 December 2014 (2). that have the same active ingredient(s). The two guidance texts are part of The Drug and Health Product Register strengthened regulation for medical is one of several initiatives undertaken as devices, including in vitro diagnostic part of Canada’s Regulatory Transparency products, in line with current international and Openness Framework. regulatory principles. ►►Government of Canada. News Release, ►►(1) CFDA Press release, 19 January 2015. 12 February 2015. (2) CFDA Press Release, 20 January 2015.

Regulatory oversight Antibiotics

FDA proposes new guidance on EMA advice on antibiotics use in compounding animals United States of America – The FDA European Union – The EMA has has released for comment five draft published recommendations to minimize documents related to compounding of antimicrobial resistance arising from the human drugs. The documents include use of antibiotics in veterinary medicines, draft guidance texts on registering an especially those that are critically outsourcing facility; adverse event important in human medicine, such as reporting by outsourcing facilities; fluoroquinolones and third and fourth repackaging of drugs; mixing, diluting and generation cephalosporins. repackaging of biological products; and

22 WHO Drug Information Vol. 29, No. 1, 2015 Regulatory news

Measures are proposed to identify public Drug availability health risks early in the product life cycle, to monitor antibiotics use and emerging Canada announces requirement for resistance, and to restrict antibiotic use in reporting of drug shortages animals in case of significant public health Canada – The Government of Canada risks. Tools are also proposed to ban or is moving towards a mandatory reporting limit the off-label use in animals of certain system that will require manufacturers to antimicrobials authorized only in human publicly report actual and anticipated drug medicine. shortages. Drug shortages are a complex The advice will serve as input into the global problem that can have devastating discussions that have now started in the consequences for certain patients. An European Council and the European advanced warning of upcoming shortages Parliament on revising the legislation on will enable Canadians to proactively work veterinary medicines. with their healthcare professionals to find ►►EMA Press release, 19 December 2014. alternative treatment options. While regulations as well as a new, independent third-party website for ECDC/EFSA/EMA first joint report this reporting are being developed, European Union – The European Centre manufacturers are expected to voluntarily for Disease Prevention and Control post information on all shortages on the (ECDC), the European Food Safety industry-run website www.drugshortages. Authority (EFSA) and the European ca, which was launched in March 2012. Medicines Agency (EMA) have published ►►Government of Canada. News release, their first integrated data analysis on 10 February 2015. antimicrobial resistance in bacteria from humans and food-producing animals. The EU industry proposal on reducing report combines data from five monitoring manufacturing-related medicines networks that gather information from shortages EU Member States, Iceland, Norway and European Union – The pharmaceutical Switzerland. industry, through its associations, has In both humans and animals, the proposed a collaborative contribution to analysis found positive associations help reduce drug shortages caused by between consumption of antimicrobials manufacturing, quality and/or GMP issues, and the corresponding resistance in a subset of the many diverse root causes bacteria for most of the combinations for shortages. The proposal encompasses investigated. Despite data limitations, communication principles as well as these findings highlight the need prevention plans both at system level and to promote the responsible use of at product level (1). antimicrobials in both humans and The proposal was made in response animals. The report will inform the to a 2012 EMA Reflection paper on European Commission’s action medicinal product supply shortages plan against the rising threats from caused by manufacturing issues (2). antimicrobial resistance. Despite existing reporting requirements ►►EMA Press release, 30 January 2015. in the EU and the U.S., drug shortages remain a global challenge. In recent years,

23 Regulatory news WHO Drug Information Vol. 29, No. 1, 2015

manufacturing- and GMP compliance- Contribution to the European Medicines Agency (EMA) and their Inspectors Working related problems have resulted in acute Group (EMA-IWG). and chronic shortages of important products. (2) EMA. Reflection paper on medicinal ►►(1) AESGP, EFPIA, EGA, ISPE, PDA and product supply shortages caused by PPTA. Prevention of Drug Shortages Based manufacturing/Good Manufacturing on Quality and Manufacturing Issues. Final Practice Compliance problems. Report. 23 December 2014. A Collaborative EMA/590745/201222. November 2012.

Approvals

Bupropion & naltrexone : for weight Liraglutide: for weight management management Product name: Saxenda® Product name: Dosage form: Once-daily injection in a pre- EU: Mysimba®; U.S.: Contrave® filled pen Dosage form: Prolonged release tablet Class: Glucagon-like peptide-1 (GLP-1) Class: Combination of an antidepressant and receptor agonist a drug used in dependence disorders; ATC code: A10BX07 ATC code (temporary classification): A08AA62 Approval: FDA, EMA Approval: EMA, FDA Use: Weight management, in combination Use: Weight management of obese adults with a reduced-calorie diet and physical or overweight adults having certain risk activity, in obese adults or overweight factors, in addition to a reduced-calorie adults with at least one weight-related diet and physical activity (prescription- health condition (prescription-only). only). Benefits: Additional treatment option for Benefits: Additional option to help chronic weight management to mitigate manage the weight-related risks for the risk of chronic health conditions. chronic diseases such as diabetes and Safety information: Some serious side effects cardiovascular disease. have been reported in patients treated Safety information: Safety and tolerability with GLP-1-based therapies, including issues have been identified relating an increased heart rate, pancreatitis, to central nervous system and gallbladder disease, renal impairment and gastrointestinal adverse events, as well suicidal thoughts. In the U.S. the product as uncertainties about cardiovascular alsohas a boxed warning against use in outcomes in the longer term. Both EMA patients with a personal or family history and FDA require some post-marketing of medullary thyroid carcinoma (MTC) or monitoring and/or risk management those with multiple endocrine neoplasia measures for this product. syndrome type 2, which predisposes them ►►EMA Press release, 19 December 2014. to MTC. Both EMA and FDA require some FDA News release, 10 September 2014. post-marketing monitoring and/or risk management measures for this product. Note: Concerns have been voiced about Notes: Liraglutide is already approved in the safety of this product, considering the U.S. and the EU at a lower dose for its potential adverse effects and past the treatment of diabetes under the trade regulatory decisions on other weight name Victoza®. management products in the EU. ►►FDA News release, 23 December 2014. ►►Prescrire Press release, 19 December 2014. EMA Press release, 23 January 2015.

24 WHO Drug Information Vol. 29, No. 1, 2015 Regulatory news

Approvals

Cangrelor : anti-clotting agent Tolvaptan: for rare kidney disease Product name: Kengrexal® Product name: Jinarc® Dosage form: Powder for concentrate for Dosage form: Tablets solution for infusion Class: Vasopressin-2-receptor antagonist Class: Platelet aggregation inhibitor ATC code: C03XA01 ATC code: B01AC25 Approval: EMA (orphan designation) Approval: EMA Use: Treatment of autosomal dominant Use: Co-administered with acetylsalicylic polycystic kidney disease (ADPKD) acid ASA, to reduce thrombotic in patients with normal to moderately cardiovascular events in adult patients reduced kidney function who have rapidly with coronary artery disease undergoing progressing ADPKD. percutaneous coronary intervention. Benefits: Ability to slow the progression of Benefits: Ability to prevent thrombotic cyst growth and renal insufficiency in adult cardiovascular events in patients patients with ADPKD who have not received oral P2Y12 Safety information: A pharmacovigilance inhibitors before percutaneous coronary plan will be implemented with additional intervention. monitoring of the risk of liver damage. ►►EMA/CHMP Opinion, 22 January 2015. Notes: This is the first medicine approved in the EU specifically for the treatment of ADPKD. Tolvaptan is already authorized

Edoxaban: anti-clotting agent in the EU under the trade same Samsca® Product name: Savaysa® for treating hyponatraemia, although the Dosage form: Tablets doses studied in ADPKD are different. Class: Anticoagulant; direct Factor Xa ►►EMA Press release, 27 February 2015. inhibitor Approval: FDA

Use: To reduce the risk of stroke and Parathyroid hormone: to systemic embolism in patients with atrial control blood calcium levels in fibrillation that is not caused by a heart hypoparathyroidism valve problem, and to treat deep vein Product name: Natpara® thrombosis and pulmonary embolism in Dosage form: Once-daily injection patients already treated with a parenteral Class: Parathyroid hormone anticoagulant for five to ten days. ATC code: H05AA03 Benefits: Similar efficacy and a lower risk of Approval: FDA (orphan drug designation) major bleeding, compared with warfarin. Use: Regulation of blood calcium levels in Safety information: Bleeding is the patients with hypoparathyroidism most serious risk with edoxaban; no Benefits: Alternative treatment option for treatment has been proven to reverse its patients whose calcium levels cannot be anticoagulant effect. controlled on calcium supplementation and The medicine carries a Boxed Warning active forms of vitamin D. on dosing and safety in specific patient Safety information: Potential risk of groups, including a warning that an osteosarcoma according to studies in alternative anti-clotting agent should rats. Only available through a restricted be used in atrial fibrillation patients programme under a Risk Evaluation and with a creatinine clearance > 95 ml/min Mitigation Strategy (REMS). (>1.58 ml/s). ►►FDA News release, 23 January 2015. ►►FDA News release, 8 January 2015.

25 Regulatory news WHO Drug Information Vol. 29, No. 1, 2015

Approvals

Ceftolozane & tazobactam : for certain complicated infections Finafloxacin: for outer ear infection Product name: Zerbaxa® Product name: Xtoro® Dosage form: Powder for intravenous Dosage form: Otic suspension infusion Class: Fluoroquinolone Class: Combination of a cephalosporin Approval: FDA antibacterial (ceftolozane) and a beta- Use: Treatment of acute outer ear infection lactamase inhibitor (tazobactam); caused by Pseudomonas aeruginosa and ATC code (temporary classification): J01DI54 Staphylococcus aureus. Approval: FDA, Qualified Infectious Disease Benefits: New antibacterial medicine with Product (QIDP) designation proven efficacy for the target conditions. Use: Treatment of adults with complicated ►►FDA News release, 17 December 2014. intra-abdominal infections and complicated urinary tract infections

Benefits: New treatment option for certain Peramivir : for influenza types of serious or life-threating infections. Product name: Rapivab® Safety information: The product label Dosage form: Single-dose intravenous includes a warning about decreased injection efficacy seen in patients with renal Class: Neuraminidase inhibitor impairment. Approval: FDA ►►FDA News release, 19 December 2014. Use: Treatment of uncomplicated influenza in adults who have had symptoms of influenza for no more than two days.

Ceftazidime & avibactam : for certain Benefits: Single-dose intravenous treatment complicated infections option for uncomplicated influenza. Product name: Avycaz® Safety information: Risk of rare but serious Dosage form: Fixed-dose combination drug skin or hypersensitivity reactions such as for injection. Stevens-Johnson syndrome and erythema Class: Combination of a previously approved multiforme. Patients with influenza may cephalosporin antibacterial (ceftazidime). be at an increased risk of hallucinations, and a new beta-lactamase inhibitor delirium and abnormal behaviour early in (avibactam). their illness and should be monitored. Approval: FDA (priority review, Qualified Note: This is the first FDA-approved Infectious Disease Product, QIDP) neuraminidase inhibitor for intravenous Use: Treatment of complicated intra- administration. abdominal infections in combination with ►►FDA News release, 22 December 2014. metronidazole, and of complicated urinary tract infections including pyelonephritis, in adult patients who have limited or no Lamivudine & raltegravir alternative treatment options. Product name: Dutrebis® Benefits: Treatment option when there are Dosage form: Film-coated tablets limited or no alternative antibacterial drugs Class: Antivirals for HIV infection for treating a patient’s infection. Use of this ATC code: J05AR16 product is reserved to such situations. Approval: EMA Safety information: Serious skin reactions Use: Treatment of HIV infection and anaphylaxis may occur in patients Benefits: Improved dosing regimen with a with penicillin allergies. reduced daily pill burden. FDA News release, 25 February 2015. ►►EMA/CHMP Opinion, 22 January 2015.

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Approvals

Meningococcal serogroup B vaccine Approval: China Food and Drug Product name: Bexsero® Administration (CFDA) Dosage form: Suspension for injection in a Use: Vaccination against poliomyelitis pre-filled syringe Benefits: This vaccine will play a critical Class: Meningococcal serogroup B vaccine role for the eradication of poliomyelitis in ATC code: J07AH09 China. (1) Approval: FDA (accelerated approval; Note: This is the second Sabin IPV to be breakthrough therapy) licensed worldwide. The Global Polio Use: Prevention of invasive meningococcal Eradication Initiative’s Eradication and disease caused by Neisseria meningitidis Endgame Strategic Plan 2013–18 calls serogroup B in individuals 10 through 25 for IPV to be introduced into immunization years of age. programmes. The CFDA-approved IPV Notes: Bexsero® is the second licensed vaccine could play an important role in meningococcal group B vaccine in the global polio eradication if it is shown to U.S., after Trumenba® licensed in October meet international quality standards. In 2014. October 2013 the first produced in China ►►FDA News release, 23 January 2015. – a vaccine against Japanese encephalitis – achieved WHO prequalification, making it acceptable for procurement Human Papillomavirus 9-valent by international organizations such as

Vaccine, Recombinant: for prevention UNICEF and the GAVI Alliance. (2) of certain cancers ►►(1) CFDA Press release, 16 January 2015. Product name: Gardasil 9® (2) China enters the global vaccine market Dosage form: Suspension for intramuscular [News]. Bulletin of the World Health injection Organization 2014;92:626-627. doi: http:// Class: Human Papillomavirus 9-valent dx.doi.org/10.2471/BLT.14.020914 Vaccine, Recombinant Approval: FDA

Use: Prevention of certain diseases caused Ceritinib: for certain lung cancers by nine types of Human Papillomavirus Product name: Zykadia® (HPV) Dosage form: Hard capsule Benefits: Added protection against five ATC code: L01XE28 additional HPV types—31, 33, 45, 52 Class: Protein kinase inhibitor and 58— which cause approximately 20 Approval: EMA (conditional marketing percent of cervical cancers and are not authorization – requirement for further covered by previously FDA-approved HPV results from ongoing studies and a vaccines. comparative phase III study within the next ►►FDA News release, 10 December 2014. three years) Use: Treatment of adult patients with anaplastic lymphoma kinase (ALK) Sabin inactivated polio vaccine positive advanced non-small cell lung (sIPV) cancer previously treated with crizotinib Product name: Ai Bi Wei (brand name in Benefits: Treatment option for a high unmet China) medical need in patients previously treated Dosage form: Injection with crizotinib, as treatment options are Class: Inactivated poliomyelitis vaccine currently very limited. (IPV), Sabin strain Safety information: The most serious adverse reactions are hepatotoxicity,

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Approvals

gastrointestinal effects, QT interval Benefits: New therapy to help slow the prolongation, bradycardia, interstitial lung progression of differentiated thyroid cancer disease/pneumonitis and hyperglycaemia. Safety information: Lenvatinib may cause ►►EMA Press release, 27 February 2015. serious side effects, including cardiac failure, blood clot formation, liver damage, kidney damage, gastrointestinal

Nivolumab: for advanced melanoma perforation or fistula formation, QT and lung cancer interval prolongation, hypocalcaemia, Product name: Opdivo® the simultaneous occurrence of Dosage form: Injection solution for headache, confusion, seizures and intravenous infusion visual changes (Reversible Posterior Class: Monoclonal antibody, PD-1 blocker Leukoencephalopathy Syndrome), ATC Code (temporary classification): L01XC17 serious bleeding, risks to an unborn child Approval: FDA (breakthrough therapy, if a patient becomes pregnant during priority review and orphan product treatment, and impairing suppression designations) of the production of thyroid-stimulating Use: Treatment of unresectable or metastatic hormone. melanoma that no longer responds to ►►FDA News release, 13 February 2015. other medicines. (1) Benefits: Additional treatment option for

patients previously treated with ipilimumab Palbociclib: for advanced breast and – in the case of patients whose cancer tumours express a BRAF V600 mutation – Product name: Ibrance® a BRAF inhibitor. Dosage form: Capsules Subsequently approved use: Treatment of Class: Antineoplastic agent; cyclin- advanced (metastatic) squamous non- dependent kinase (CDKs) 4 and 6 inhibitor small cell lung cancer with progression on Approval: FDA (accelerated approval, or after platinum-based chemotherapy. (2) breakthrough therapy) Safety information: The most serious adverse Use: Treatment of certain metastatic breast effects are severe immune-mediated cancers in postmenopausal women who side effects involving healthy organs, have not yet received an endocrine- including the lung, colon, liver, kidneys and based therapy. Palboclicib is to be used in hormone-producing glands. combination with letrozole (Femara®) ►►(1) FDA News release, 22 December 2014. Benefits: New treatment option for certain (2) FDA News release, 4 March 2015. types of metastatic breast cancer. ►►FDA News release, 3 February 2015.

Lenvatinib: for certain progressive thyroid cancers Safinamide: for Parkinson’s disease Product name: Lenvima® Product name: Xadago® Dosage form: Capsules Dosage form: Film-coated tablets Class: Kinase inhibitor Class: Selective and reversible monoamine ATC Code (temporary classification): L01XE29 oxidase B (MAO-B) inhibitor Approval: FDA (priority review) Approval: EMA Use: Treatment of patients with progressive, Use: Treatment of adult patients with differentiated thyroid cancer whose idiopathic Parkinson’s disease as add-on disease progressed despite receiving therapy radioactive iodine therapy

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Approvals

Benefits: Ability to prolong the times during Class: Ex-vivo expanded autologous human which symptoms are adequately controlled corneal epithelial cells containing stem (“on” times) in patients with motor cells, ophthalmological product fluctuations receiving L-dopa alone or in ATC code: S01XA19 combination with other medications for Approval: EMA (orphan designation) Parkinson’s disease. Use: Treatment of moderate to severe limbal ►►EMA/CHMP Opinion, 19 December 2014. stem cell deficiency due to physical or chemical burns to the eye(s) in adults. Benefits: Ability to repair the damaged ocular

Autologous limbal stem cells : for surface, to improve or resolve symptoms limbal stem cell deficiency due to of pain, photophobia and burning, and to burns to the eyes ; improve the patient’s visual acuity. Product name: Holoclar® Note: This is the first stem-cell therapy Living tissue equivalent intended to be recommended for approval in the EU. transplanted in the affected eye(s), made ►►EMA News, 19 December 2014. from a biopsy taken from the patient’s cornea and grown in cell culture.

Extensions of indications

Related reading: Adaptive licensing pathways, page 32.

Product Newly approved indication Reviewing authority reference Lenalidomide Continuous treatment of adult ►►EMA/CHMP Opinion, (Revlimid®) patients with previously untreated 18 December 2014. Hard capsule multiple myeloma who are not eligible for transplant. Bevacizumab In combination with paclitaxel and ►►EMA/CHMP Opinion, (Avastin®) cisplatin or, alternatively, paclitaxel 26 February 2015. Concentrate for and topotecan in patients who solution for intravenous cannot receive platinum therapy, for infusion the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix. Paclitaxel In combination with carboplatin, first- ►►EMA/CHMP Opinion, (Abraxane®) line treatment of non-small cell lung 22 January 2015. Powder for suspension cancer in adult patients who are not for infusion candidates for potentially curative surgery and/or radiation therapy. Continued

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Extensions of indications

Continued Product Newly approved indication Reviewing authority reference Ibrutinib Treatment of Waldenström’s FDA (breakthrough therapy, (Imbruvica®) macroglobulinaemia, a rare form priority review, and orphan Capsules of cancer that begins in the body’s product designation) immune system. Note: This is the first drug approved worldwide specifically ►►FDA News release, for treatment of Waldenström’s 29 January 2015. macroglobulinaemia. Bortezomib In combination with rituximab, ►►EMA/CHMP Opinion, (Velcade®) cyclophosphamide, doxorubicin 18 December 2014. Powder for solution for and prednisone treatment of adult injection patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation. Ramucirumab Treatment of metastatic non-small FDA (priority review) cell lung cancer, in combination with (Cyramza®) ►►FDA News release, Concentrate for docetaxel. 12 December 2014. solution for infusion Lisdexamfetamine Treatment of binge eating disorders FDA (priority review) in adults - first FDA-approved dimesylate ►►FDA News release, (Vyvanse®) medication to treat this condition. 30 January 2015. Capsules Safety information: The most serious risks include psychiatric problems and heart complications. Lisdexamfetamine is a Schedule II controlled substance in the U.S. because of its high potential for abuse. Ranibizumab Treatment of diabetic retinopathy FDA (breakthrough therapy (Lucentis®) in patients with diabetic macular designation, priority review) Injection oedema. The drug is intended to be used together with appropriate interventions to control blood sugar, ►►FDA News Release, blood pressure and cholesterol. 6 February 2015. Safety information: Endophthalmitis and retinal detachments are the two most serious side effects associated with ranibizumab. Continued

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Extensions of indications

Continued Product Newly approved indication Reviewing authority reference Palonosetron Prevention of acute nausea and ►►EMA/CHMP Opinion, (Aloxi®) vomiting associated with highly 22 January 2015. Solution for injection emetogenic cancer chemotherapy, and prevention of nausea and vomiting associated with moderately emetogenic cancer chemotherapy in paediatric patients 1 month of age and older.

Labelling changes

Diabetes pen devices : for single- Xpert® MTB/RIF test: can guide patient use only decisions on ending patient isolation; Product: Multi-dose diabetes pen devices Product name: Xpert® MTB/RIF Assay Regulatory authority: FDA Test type: Nucleic acid amplification test Labelling change: The FDA requires that to detect M. tuberculosis complex and pens and packaging containing multiple genetic markers for rifampicin resistance. doses of insulin and other injectable Regulatory authority: FDA diabetes medicines display a warning Labelling change: Revised labelling label stating “For single patient use only.” states that the results from one or two Additional warnings against sharing pens consecutive negative MTB/RIF tests will also be added to the prescribing strongly predict the results that would information and to the patient Medication be obtained from acid-fast bacilli smear Guides, Patient Package Inserts, and testing of three sputum specimens Instructions for Use. collected eight to 24 hours apart. Results Note: Even if the needle is changed insulin from one or two MTB/RIF tests (depending pens and pens for other injectable on the specific patient being tested and diabetes medicines should never be hospital guidelines) can be used in the shared among patients, as blood may decision to remove patients from airborne be present in the pen after use. The infection isolation. requirement was introduced to reduce the Caution: the MTB/RIF test may not detect serious risk of infection spread through all patients with active tuberculosis (TB). sharing of multi-dose diabetes pen The FDA advises that healthcare workers devices. should also continue to follow current CDC ►►FDA Drug safety communication, guidelines to collect consecutive sputum 25 February 2015. specimens for TB culture testing, even if results from MTB/RIF testing are negative. ►►FDA News release, 12 February 2015. æ

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Publications and events

Access to treatment Appraisal of expensive medicines An editorial in the Bulletin of the World Adaptive licensing pathways Health Organization presents the case for A recent publication takes a look at the a global forum to discuss objectivity and environmental changes that may make equity in access to high-priced drugs. adaptive licensing pathways the approach Increasingly, patients are asking for of the future. early access to new drugs, for example The concept of adaptive licensing to treat cancer. Often these drugs are foresees an early approval of a medicine very expensive. Price-setting is largely for a restricted patient population, a function of the market, and the prices based on small initial clinical studies. of some recently introduced drugs – The initial marketing authorization is for example sofosbuvir – have been then progressively adapted to make the questioned. medicine accessible to broader patient The authors argue that it is time for populations, based on data gathered from a global forum for the development of its use and from additional studies. methods to evaluate available data Key drivers that could make adaptive for early market entry, determine an pathways the preferred approach in future appropriate initial price, optimize the include: growing patient demand for timely collection of data from clinical practice, access to promising therapies in particular enable independent trials and manage the where there are unmet medical needs; exit of products that, in practice, are found identification of subgroups of patients who to be insufficiently effective. are likely to respond to certain medicines ►►Hill SR, Bero L, McColl G, Roughead E. better than others; rising payer influence Expensive medicines: ensuring objective with calls for a more targeted use of appraisal and equitable access. Bulletin of medicines to increase their therapeutic the World Health Organization 2015;93:4. value; and pressure on industry and doi: http://dx.doi.org/10.2471/BLT.14.148924 investors to make drug development sustainable by targeting smaller, better defined patient populations to bring BRICS Ministers tackle priority medicines forward at a lower initial cost. diseases ►►EMA News, 15 December 2014. Brasília – At their Meeting held on 4-5 Eichler HG, Baird LG, Barker R. et al. From December 2014, Ministers of Health adaptive licensing to adaptive pathways: from Brazil, Russia, India, China and Delivering a flexible life-span approach to South Africa (BRICS) reaffirmed their bring new drugs to patients. Clin Pharmacol commitment to fight priority diseases. Ther. Accepted Article, 12 December 2014. They committed to ambitious doi: 10.1002/cpt.59 tuberculosis targets and approved the development of a plan to achieve universal access to first line

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anti-tuberculosis medicines in BRICS and Medicines Patent Pool signs low- and middle-income countries. The licensing agreements for paediatric plan will include common approaches antiretrovirals to promote research and innovations on Geneva – The Medicines Patent tuberculosis diagnostics and treatment, Pool (MPP) has signed two new share technologies, and identify licensing agreements for HIV paediatric manufacturing capacities and means of formulations, enabling pharmaceutical financing. companies to develop, manufacture and The Ministers also committed to sell low-cost product versions in countries ambitious HIV treatment targets to end with high disease burdens. the AIDS epidemic as a global threat by An agreement has been signed 2030, and they reaffirmed their support to with AbbVie for lopinavir and ritonavir, initiatives to overcome barriers in access covering 102 countries of which more to medicines. than 65 are classified as middle-income They further expressed their support nations. Moreover, provisions in the for WHO global action plans to stop agreement permit manufacture and the Ebola outbreak, to fight neglected distribution in countries where AbbVie tropical diseases, to reduce antimicrobial does not hold patents, such as in India resistance, and to fight non-communicable where the company has withdrawn its diseases. patent applications for both lopinavir and ►►IV Meeting of the BRICS. Joint ritonavir. (1) Communiqué. 5 December 2014. An agreement has also been signed with MSD, known as Merck in the United States and Canada. The agreement is LDCs request extension of for paediatric formulations of raltegravir intellectual property rights waiver and covers 92 low- and middle-income for medicines countries. Raltegravir fills an important Geneva – At the World Trade Organization gap in the care of children who fail on their (WTO) intellectual property committee first-line HIV regimens.(2) meeting held on 24-25 February 2015 a The licenses will support the work of group of least-developed countries (LDCs) the recently launched Paediatric HIV have proposed to extend the current Treatment Initiative (PHTI) to develop waiver to intellectual property rights better adapted medicines for children enforcement for pharmaceutical products living with the virus. past the deadline of 2016, until they are no The MPP cooperates with the WHO longer considered LDCs. Prequalification of Medicines Programme LDCs are disproportionately exposed to to ensure that medicines made with MPP the health risks associated with poverty. In licences meet international quality and its statement the group notes that “patent safety standards and are acceptable for protection contributes to high costs, UN procurement. placing many critical treatments outside ►►(1) MPP Press release, 1 December 2014. the reach of LDCs”. (2) MPP Press release, 24 February 2015. ►►WTO News, 24 February 2015. IP Watch post, 25 February 2015.

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Anti-TB drug donation agreed with the University of Auckland and Geneva – The United States Agency for University of Illinois-Chicago. In preclinical International Development (USAID) and studies, TBA-354 demonstrated more the Johnson & Johnson affiliate Janssen potent anti-bactericidal and sterilizing Therapeutics have signed a memorandum activity than pretomanid, another of understanding to provide 30 000 nitroimidazole drug that is currently being treatment courses of the newly developed tested as a component of other novel medicine bedaquiline worth US$ 30 million regimens in multiple clinical trials. for free through USAID’s programmes. The TB Alliance is a not-for-profit The medicine will be distributed to nearly organization dedicated to finding faster- 100 eligible low- and middle-income acting and affordable drug regimens countries over four years. Eligibility criteria to fight tuberculosis through innovative will be developed over the coming months. science with support from partners around Bedaquiline is the first new anti- the globe. tuberculosis drug developed in four ►►TB Alliance News release, 18 February 2015. decades. It is effective against strains of tuberculosis that are resistant to two or more antibiotics. Disease updates The Executive Secretary of the Stop TB Partnership, Dr Ditiu, noted that the Ebola: an unforgiving virus community should use this opportunity Geneva – One year after the first Ebola wisely to save lives, and that the deal cases emerged in Guinea, WHO has sets a precedent for collaboration released a series of 14 papers that take between pharmaceutical companies and an in-depth look at different aspects of the international organizations to tackle drug- epidemic (1). resistant tuberculosis. ►►USAID Press release, 11 December 2014. Vaccines Stop TB Partnership News, 12 December As the epidemic begins to ebb, efforts to 2014. develop, test, and approve Ebola vaccines are followed through as they will have a significant impact on the further evolution. Product development Two vaccines are at an advanced stage of developmen; large volumes of vaccine New anti-tuberculosis medicine doses could become available from early starts clinical testing 2015 although deployment and further New York – The Global Alliance for TB evaluation in the aftermath of the outbreak Drug Development (TB Alliance) has will be demanding (2). The first Phase III announced the start of the first human trial trial was launched in Guinea in March of a new tuberculosis drug candidate, a 2015 (3). A third vaccine candidate is in next-generation nitroimidazole designated Phase I trials and a number of others are TBA-354. It is the first new TB drug under development (4). candidate to begin a Phase I clinical trial since 2009. Treatments TBA-354 was identified in studies Convalescent blood therapies and conducted by TB Alliance in collaboration medicines have been further evaluated.

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Two medicines approved for other uses longer term for the world to respond – favipiravir and brincidofovir – warrant to health emergencies under WHO’s further investigation in clinical trials in leadership. (8) affected countries (2). The EMA has ►►(1) WHO. One year into the Ebola epidemic: reviewed seven medicine candidates to a deadly, tenacious and unforgiving virus. treat Ebola, and has found that available January 2015. evidence is not sufficient to draw con­ (2) WHO. Modernizing the arsenal of control clusions on their safety and efficacy(5) . tools: Ebola vaccines. January 2015. (3) WHO/MSF/NIPH Joint news release, Diagnostics 5 March 2015. WHO has established an emergency (4) WHO Essential medicines and health quality assessment mechanism for products. WHO Ebola R&D Effort – vaccines, therapies, diagnostics [web page]. in vitro diagnostics (IVDs) for Ebola 30 January update. Virus Disease. The mechanism aims to (5) EMA Press release, 16 December 2014. identify products that are acceptable for (6) WHO. In vitro diagnostics and laboratory procurement by UN organizations and technology. Emergency Use Assessment other partners while further data are being and Listing (EUAL) Procedure for Ebola developed. In November 2014 WHO Virus Disease (IVDs) [web page]. accepted the first Ebola in vitro diagnostic (7) WHO. Ebola response: what needs to product under this mechanism; the first happen in 2015. January 2015. rapid test followed in February 2015. (8) WHO Executive Board Special Session Other products are under assessment. on Ebola. EBSS3.R1. Ebola: ending the WHO is working with the Foundation current outbreak, strengthening global for Innovative New Diagnostics (FIND), preparedness and ensuring WHO’s capacity to prepare for and respond to future large- Médecins Sans Frontières (MSF), scale outbreaks and emergencies with manufacturers and regulators to guide the health consequences. 25 January 2015. development of new tests. (6)

The way forward Non-communicable diseases: Four main lessons have been learned preventable early deaths from this largest and longest Ebola Geneva – WHO has launched its global outbreak in history: Firstly, resilient health status report on noncommunicable systems must be built in all countries to diseases (NCDs) for 2014. The report absorb the shocks of future epidemics and calls for government action to reduce climate changes. Secondly, vigilance and the annual toll of 16 million premature preparedness make a huge difference. deaths – before the age of 70 – from heart Thirdly, a host of control measures must and lung diseases, stroke, cancer and be coordinated to fight disease outbreaks, diabetes. 82% of these deaths occur in and lastly, community engagement is low- and middle-income countries. essential for an effective response. (7) The report outlines a plan with nine At a special session held in January voluntary global targets to address key 2015 the WHO Executive Board NCD risk factors. It identifies “best buy” unanimously adopted a comprehensive cost-effective preventive interventions resolution on next steps to end the Ebola to reduce tobacco use, salt intake, outbreak and on what is needed in the physical inactivity, high blood pressure

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and harmful use of alcohol. Targets are the target defined in the WHO Global TB also set for access to drug therapy and strategy, which is to eliminate tuberculosis counselling – including glycaemic control as a public threat by 2035. – to prevent heart attacks and strokes, ►►(1) WHO. Global Tuberculosis Report 2014. and for availability of affordable basic (2) Zumla A et al. The WHO 2014 Global technologies and essential medicines – tuberculosis report – further to go. The including generics – to treat major NCDs Lancet Global Health , Volume 3 , Issue 1 , in both public and private facilities. e10 - e12. ►►WHO News release, 19 January 2015.

Malaria: fragile gains Tuberculosis: further to go London – The World Malaria Report Geneva – Improved data show that there 2014, launched in the United Kingdom are almost half a million more tuberculosis Houses of Parliament in December 2014, cases worldwide than previously shows some encouraging results. The estimated. According to the WHO Global number of people dying from malaria has Tuberculosis Report 2014 (1) nine million fallen dramatically since 2000, and malaria people developed tuberculosis in 2013, cases are also steadily declining. Between and 1.5 million died. Encouragingly, 2000 and 2013, the malaria mortality rate incidence and mortality rates are still decreased by 47% worldwide and by 54% falling, and an estimated 37 million in the WHO African Region, where about lives have been saved through effective 90% of malaria deaths occur. diagnosis and treatment since 2000. While biological and technical Nevertheless a staggering number of challenges remain, a strong pipeline lives continue to be lost to this curable of innovative new products has the disease. Around three million tuberculosis potential to transform malaria control and cases are still being missed by health elimination. However, despite a threefold systems each year because they are increase since 2005, funding to combat either not diagnosed or not reported. malaria is still only around half of the The multidrug-resistant tuberculosis US$ 5.1 billion needed to achieve global (MDR-TB) crisis continues, with severe targets. (1) epidemics in some regions and low Adequate resourcing is particularly treatment success rates in many settings important to contain the parasite around the world. Extensively drug- resistance to antimalarials that now resistant tuberculosis (XDR-TB), which is affects five Asian countries. A recent study even more expensive and difficult to treat found that resistant strains have spread than MDR-TB, has now been reported throughout Myanmar and have reached in 100 countries. The report includes a the border with India. If resistant malaria supplement that marks 20 years of anti-TB spreads to Africa, millions of lives could be drug-resistance surveillance and outlines at risk. (2) the MDR-TB response and priority actions. ►►(1) WHO News release, 9 December 2014. The authors of a comment in The Lancet (2) Tun KM et al. Spread of artemisinin- (2) have called on all governments and resistant Plasmodium falciparum in donors to increase their funding for urgent, Myanmar: a cross-sectional survey of swift, and visionary action to reach the the K13 molecular marker. Lancet Infect

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Dis 2015. Published online, 20 February Organization urges affected countries 2015. http://dx.doi.org/10.1016/S1473- 3099(15)70032-0. to scale up their investment in tackling 17 neglected tropical diseases in order to improve the health and well-being of more HIV: fast track targets than 1.5 billion people. This investment Geneva/Los Angeles – A UNAIDS would represent as little as 0.1% of current flagship report launched during an event domestic expenditure on health in affected at the University of California, Los Angeles low- and middle-income countries for the (UCLA) in November 2014 shows how the period 2015-2030. world can now build on past achievements Neglected tropical diseases cause to end the AIDS epidemic as a global blindness, disfigurement, permanent health threat. disability and death. While good progress By the end of 2013, 35 million people has been made towards eliminating were living with HIV worldwide. New some of them, others are gaining HIV infections in 2013 were estimated at ground because of rapid and unplanned 2.1 million, which was 38% lower than in urbanization, population movement and 2001. The number of AIDS-related deaths environmental change. Dengue is one also continues to decline, with 1.5 million of them: it is now present in more than people dying of AIDS-related causes in 150 countries. The report outlines an 2013, down 35% from the peak in 2005. investment case and essential package of There is a global consensus to aim for interventions for each of the 17 neglected 90% of people living with HIV knowing tropical diseases targeted by WHO. their HIV status, 90% of people who ►►WHO News release, 19 February 2015. know their status receiving treatment and 90% of people on HIV treatment having a suppressed viral load thus reducing the risk of transmission. Other targets WHO matters include reducing the annual number of new HIV infections by more than 75%, MQAS procurement guidelines now to 500 000 in 2020, and achieving zero available in French discrimination. Investments will be critical Geneva – The 2014 revisions of two in achieving these targets. Particular procurement-related WHO guidelines are efforts are needed in the 30 countries now also available in French: The Model that together account for 89% of new HIV quality assurance system for procurement infections worldwide, requiring significant agencies (1) and the Assessment tool commitments from both national and based on the model quality assurance international sources. system for procurement agencies: aide- ►►UNAIDS Press release, 18 November 2014. memoire for inspection (2). These guidelines are widely used by international organizations to assure the Neglected tropical diseases: quality of the health products that they domestic investments needed; purchase or finance globally. Geneva – WHO has released its report ►►(1) Système modèle d’assurance de la Investing to overcome the impact qualité pour agences d’approvisionnement. of neglected tropical diseases. The Dans : WHO Expert Committee on

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Specifications for Pharmaceutical Within the wide range of quality assurance Preparations, forty-eighth report. Genève, OMS, 2014 (Série de rapports techniques measures that are needed to help ensure de l’OMS, N° 986), Annexe 3. that quality medicines reach the patient, (2) Outil d’évaluation des AA fondé sur quality control has traditionally been one le Système modèle d’assurance de la of the key elements. Pharmaceutical qualité pour AA: aide-mémoire pour les quality control laboratories play a major inspections. Dans : WHO Expert Committee role in protecting patients from harm. on Specifications for Pharmaceutical Quality control (QC) testing is Preparations, forty-eighth report. Genève, OMS, 2014 (Série de rapports techniques complex. Errors are not only costly but de l’OMS, N° 986), Annexe 4. may jeopardize patient safety. Patients Note: To complement the two WHO guidelines may receive ineffective or even harmful a self-assessment tool on compliance with medicines if true quality deficiencies MQAS principles has been published in WHO are not identified. Conversely, if non- Drug Information, Vol. 28, No. 4). An Excel conforming results are falsely interpreted version is available from [email protected]. as quality failures, expensive medicines may be returned or destroyed, potentially leaving patients without life-saving Do you manufacture these APIs? treatment until the products are replaced We are interested in you at sometimes enormous additional costs. The World Health Organization’s Given these high stakes, trust in a QC prequalification scheme gives free help laboratory’s capabilities is essential for all to manufacturers of selected active stakeholders who request its services. pharmaceutical ingredients (APIs), medicines and vaccines who want New phase of EQAAS to boost their standards and access WHO is pleased to announce Phase 6 international markets. of its External Quality Assurance Read this article for more details: Assessment Scheme (EQAAS) at ►►in-Pharma Technologist.com. Free preferential fees far below cost for Newsletter. Article from CPHI India, 2014. participants from lower- and middle- Fiona Barry, 4 December 2014. income countries. In order to enhance the Note: The 7th Invitation for API manufacturers efficiency and save costs, two studies will to submit an Expression of Interest (EOI) be carried out for each shipment. Fees are for evaluation of their API by the WHO Prequalification Team - Medicines is available at: based on the World Bank classification of http://apps.who.int/prequal/info_applicants/eoi/ income and are as follows: API-EOI_V7_1.pdf. • Laboratories in low-income countries: US$ 1000 • Laboratories in middle-income countries: New phase of WHO’s external US$ 2000 quality control laboratory scheme • Laboratories in high-income countries: US$ 4000 The important role of QC laboratories The above fees cover shipment of test Quality of medicines is a major public samples for two studies, together with health challenge, particularly in light of the study protocols and the subsequent the cross-border health-related issues statistical evaluation of the submitted and the international dimensions of trade. results. WHO informs the laboratories

38 WHO Drug Information Vol. 29, No. 1, 2015 Publications and events

about their performance and provides 60 laboratories across WHO’s six regions, additional guidance for improving their many of them in Africa, have participated capabilities. The scheme is set out in in its past comparative external close cooperation with related WHO assessment studies. Participation in such programmes, including the programme studies is mandatory according to WHO dealing with the prequalification of QC good practices for pharmaceutical quality laboratories. control laboratories and for ISO 17025 accreditation. Funding ►►For more information and expression of International donors may be approached interest to participate in this new phase for funding of participation in the of WHO’s QC laboratory scheme, please contact WHO at: [email protected]. EQAAS. The Global Fund to Fight AIDS, Tuberculosis and Malaria encourages grant applicants to include this item in their applications for funding. The Global WHA resolutions now on official Fund requires grant recipients to arrange record systematic random QC testing of products Geneva – The Sixty-seventh World Health throughout the in-country supply chain for Assembly (WHA), held in May 2014, medicines worth about US$ 600 million adopted a total of 25 resolutions, including delivered to grant-funded programmes two with particular relevance to medicines every year. It also funds large quantities of regulation. Resolution WHA67.20 urges laboratory equipment and reagents. Other Member States and WHO to work together donors have similar policies. to strengthen national regulatory systems WHO invites laboratories to participate around the world, while Resolution in EQAAS Phase 6 studies. To ensure WHA67.21 emphasizes the need for continued assistance to laboratories in updated norms and regulations for Member States, WHO will offer advice biotherapeutic and biosimilar products. on possible funding sources through This new generation of medicines holds WHO country projects for laboratories great promise if they can be put within the in developing countries that have no reach of all who need them. means to recuperate the fee, and for The final wording of the Sixty-seventh whom the fee represents an obstacle for World Health Assembly’s resolutions is participation. now available in WHO’s official online records of resolutions and decisions More about EQAAS (http://apps.who.int/gb/or/). The two WHO at present offers the only global, above-mentioned resolutions are independent scheme to measure reproduced on the following pages for laboratories’ QC testing capabilities. The easy reference. EQAAS was established by WHO in 2000 ►►World Health Assembly. Resolution at the request of the Global Fund as a WHA67.20. Regulatory system strengthening mechanism to maximize health benefits for medical products. 24 May 2014. achieved with grant investments in ►►World Health Assembly. Resolution pharmaceuticals and laboratory supplies. WHA67.21. Access to biotherapeutic products including similar biotherapeutic products and The EQAAS has proven to be a major ensuring their quality, safety and efficacy. 24 asset to WHO Member States. More than May 2014.

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WHA Resolutions

WHA67.20: Regulatory system strengthening for medical products1

The Sixty-seventh World Health Assembly, Having considered the report on regulatory system strengthening; 2 Welcoming the efforts of the Director-General, and recognizing the pivotal role that WHO plays in supporting countries in strengthening their regulatory systems of medical products for human use,3 and in promoting equitable access to quality, safe, efficacious and affordable medical products; Recalling the Constitution of the World Health Organization, which affirms that the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition; Recalling also United Nations General Assembly resolution 67/81 on global health and foreign policy, which, inter alia, recognized the importance of universal coverage in national health systems, especially through primary health care and social protection mechanisms, in the provision of access to health services for all, in particular for the poorest segments of the population; Recalling further resolutions WHA45.17, WHA47.17, WHA52.19, WHA54.11, WHA59.24, WHA63.12 and WHA65.19, all of which encompass aspects of the need to promote the quality, safety, efficacy and affordability of medicines, including blood products; Reaffirming resolution WHA65.19 on substandard/spurious/falsely-labelled/falsified/ counterfeit medical products, which establishes a new Member State mechanism for international collaboration, from a public health perspective, excluding trade and intellectual property considerations, to prevent and control substandard/spurious/falsely-labelled/falsified/ counterfeit medical products and to promote access to affordable, safe and quality medical products; Recognizing that effective regulatory systems are an essential component of health system strengthening and contribute to better public health outcomes, that regulators are an essential part of the health workforce, and that inefficient regulatory systems themselves can be a barrier to access to safe, effective and quality medical products; Recognizing also that effective regulatory systems are necessary for implementing universal health coverage, responding to the dual burden of infectious and noncommunicable diseases, and achieving Millennium Development Goal 4 (Reduce child mortality), Goal 5 (Improve maternal health) and Goal 6 (Combat HIV/AIDS, malaria and other diseases); Aware that health systems need to promote access to essential medical products and that, in order to ensure universal access to health care, rational use of medicines and the sustainability of health systems, urgent action is needed by the international community, Member States and relevant actors in health systems; Very concerned by the impact on patients of medical products of compromised quality, safety and efficacy, in terms of poisoning, inadequate or no treatment, contributions to drug resistance, the related economic burden, and erosion of public trust in the health system;

1 See Annex 6 for the financial and administrative implications for the Secretariat of this resolution. 2 Document A67/32. 3 For the purpose of this resolution, medical products include medicines, vaccines, diagnostics and medical devices.

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WHA Resolutions

Aware of the regulatory challenges presented by the ever-increasing complexities of medical product supply chains and welcoming the work plan of the Member State mechanism on substandard/ spurious/falsely-labelled/falsified/counterfeit medical products; Emphasizing WHO’s role in strengthening regulatory systems for medical products from a public health perspective, and in supporting national drug regulatory authorities and relevant regional bodies in this area, and in particular in developing countries; Recalling the WHO global strategy and plan of action on public health, innovation and intellectual property, in particular element three, which calls for establishing and strengthening regulatory capacity in developing countries as one effective policy for building and improving innovative capacity, and element six, which promotes establishing and strengthening mechanisms to improve ethical review and regulate the quality, safety and efficacy of health products and medical devices; Noting with appreciation the many existing national and regional efforts to strengthen regulatory capacity (including through a variety of models), improve regulatory coherence and convergence among regulatory authorities, and enhance good governance, including transparency in decision-making, leading to the improved availability of quality, safe, efficacious and affordable medical products, such as the European Union regulatory framework for medical products, work under way in PAHO following the adoption by its Directing Council in 2010 of resolution CD50.R9 on strengthening national regulatory authorities for medicines and biologicals, the African Medicines Regulatory Harmonization Initiative, and the regulatory harmonization and cooperation work in ASEAN; Noting the ongoing collaboration between national and regional regulatory authorities in promoting cooperation among regulatory authorities at the regional and global levels; Recognizing the significant investments made in the procurement of medicines through national health budgets and global health initiatives; Also recognizing the essential role of WHO’s prequalification programme in facilitating procurement of medical products with assured quality, safety and efficacy; Stressing that the strengthening of regulatory systems should complement the efforts of the Secretariat and Member States to promote access to affordable medical products with assured quality, safety and efficacy; Recalling the WHO good clinical practices that focus on the protection of human research subjects; Recalling also WHO’s ongoing reform agenda and welcoming in this regard the establishment in November 2012 of the Health Systems and Innovation cluster, 1. URGES Member States:4 (1) to strengthen national regulatory systems, including – as appropriate and voluntarily – by: (a) undergoing self-evaluations, including with WHO’s support, to identify the strengths and opportunities for improvement in regulatory system functions, as a first step towards formulating plans for regulatory system strengthening, including through WHO- coordinated institutional development plans;

4 And, where applicable, regional economic integration organizations.

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WHA Resolutions

(b) collecting data on regulatory system performance to enable analysis and benchmarking for improved systems in the future; (c) developing strong legal foundations and political leadership to underpin a regulatory system with a clear focus on patient safety and transparency in decision-making; (d) identifying and developing a core set of regulatory functions to meet country and/or regional needs, such as market control and postmarket surveillance; (e) developing needed competencies as an integral part of, although not limited to, the health workforce, and encouraging the development of the regulatory field as a profession; (f) facilitating the use of relevant guidance and science-based outputs of WHO expert committees and good regulatory practices at the national, regional and international levels; (g) devising and implementing strategies to address the increasing complexities of supply chains; (2) to engage in global, regional and subregional networks of national regulatory authorities, as appropriate, recognizing the importance of collaboration to pool regulatory capacities to promote greater access to quality, safe, efficacious and affordable medical products; (3) to promote international cooperation, as appropriate, for collaboration and information sharing, including through electronic platforms; (4) to support regulatory systems for medical products with appropriate funding as an essential component of the health system; (5) to support regulatory system strengthening as an essential component of the development or expansion of local or regional production of quality, safe and efficacious medical products; (6) to achieve access to and rational use of quality, safe, efficacious and affordable essential medicines, noting the growing emergence of resistance, and as a foundation for achieving broader access to quality, safe, efficacious and affordable medical products; (7) to support WHO’s institutional capacity relating to promoting access to and rational use of quality, safe, efficacious and affordable medical products in the context of universal health coverage; (8) to strengthen the national and regional initiatives of regulatory authorities to improve regulatory capacities for review of medical products, promoting WHO’s long-term objective of supporting the strengthening of national regulatory authority capacity among Member States; (9) to support WHO’s prequalification programme, including exploring modalities in consultation with Member States5 for improved sustainability of this critical programme; (10) to identify the need to strengthen regulatory system capacity, collaboration and cooperation in the technically complex areas where substantial gaps may still exist, such as the regulation of biotherapeutic products, blood products, and in vitro diagnostics; 2. REQUESTS the Director-General: (1) to continue to support Member States, upon their request, in the area of regulatory system strengthening, including, as appropriate, by continuing to: 5 And, where applicable, regional economic integration organizations.

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WHA Resolutions

(a) evaluate national regulatory systems; (b) apply WHO evaluation tools; (c) generate and analyse evidence of regulatory system performance; (d) facilitate the formulation and implementation of institutional development plans; (e) provide technical support to national regulatory authorities and governments; (2) to continue to develop appropriate norms, standards and guidelines, taking into account national, regional and international needs and initiatives, in accordance with WHO principles; (3) to ensure that all relevant parts of the Organization, at all levels, are actively engaged and coordinated in the carrying out of WHO’s mandate pertaining to regulatory system strengthening as an integrated part of health system development, recognizing that WHO’s support in this critical area, particularly for developing countries, may be required, as appropriate, well into the future; (4) to prioritize support for establishing and strengthening regional and subregional networks of regulatory authorities, as appropriate, including strengthening areas of regulation of health products that are the least developed, such as regulation of medical devices, including diagnostics; (5) to promote the greater participation of Member States in existing international and regional initiatives for collaboration and cooperation in accordance with WHO principles and guidelines; (6) to strengthen WHO’s prequalification programme, including its integration and coherence, taking into account the needs and capacities of national and regional regulatory systems to assist in ensuring a supply of quality, safe, efficacious and affordable medical products; (7) to support the building-up of effective national and regional regulatory bodies and networks; (8) to increase support for and recognition of the significant role of the International Conference of Drug Regulatory Authorities in promoting the exchange of information and collaborative approaches among drug regulatory authorities, and as a resource to facilitate further development of regulatory cooperation and coherence; (9) to raise awareness of the importance of effective regulatory systems within the health system context; (10) to increase support and guidance for strengthening the capacity to regulate increasingly complex biological products, with the focus on biotherapeutic products, blood products and associated in vitro diagnostics, and, where appropriate, on new medicines for human use based on gene therapy, somatic-cell therapy and tissue engineering; (11) to ensure that any activity carried out under this resolution does not duplicate or circumvent the work plan and mandate of the Member State mechanism on substandard/ spurious/falsely-labelled/falsified/counterfeit medical products; (12) to report to the Seventieth and Seventy-second World Health Assemblies on progress in the implementation of this resolution. (Ninth plenary meeting, 24 May 2014 – Committee B, fourth report)

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WHA Resolutions

WHA67.21: Access to biotherapeutic products, including similar 1 2 biotherapeutic products, and ensuring their quality, safety and efficacy ;

The Sixty-seventh World Health Assembly, Having considered the report on regulatory system strengthening;3 Recalling the Constitution of the World Health Organization, which affirms that the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition; Noting with particular concern that for millions of people, the right to the enjoyment of the highest attainable standard of physical and mental health, including access to medicines, remains a distant goal; that especially for children and those living in poverty, the likelihood of achieving this goal is becoming increasingly remote; that millions of people are driven below the poverty line each year because of catastrophic out-of-pocket payments for health care; and that excessive out-of-pocket payments can discourage the impoverished from seeking or continuing care; Recalling resolution WHA55.14 on ensuring accessibility of essential medicines, which recognizes the responsibility of Member States to support solid scientific evidence, excluding any biased information or external pressures that may be detrimental to public health; Further recalling that in resolution WHA55.14 the Health Assembly urged Member States, inter alia, to reaffirm their commitment to increasing access to medicines, and to translate such commitment into specific regulation within countries, especially enactment of national drug policies and establishment of lists of essential medicines based on evidence and with reference to WHO’s Model List, and into actions designed to promote policy for, access to, and quality and rational use of, medicines within national health systems; Considering that one of the objectives of pharmaceutical regulation is the assurance of the quality, safety and efficacy of pharmaceutical products through the regulatory processes of authorization, vigilance and monitoring; Considering also that national pharmaceutical regulation should contribute to the performance and sustainability of health systems and the general welfare of society; Considering further that an update of the norms and standards applicable to medicines is required in the light of advances made in biotechnology, and the new generation of medicines introduced as a result, in order to ensure the entry into the market of medicines that are affordable, safe, efficacious, of quality and accessible in a timely and adequate fashion; Recognizing that the use of such medicines has a positive impact on morbidity and mortality rates and that, while there are multiple barriers to access, the high cost of such medicines affects the sustainability of health systems and could in many cases affect access to them; Noting the importance of, and using as appropriate, WHO’s Expert Committee on Biological Standardization’s guidelines on evaluation of similar biotherapeutic products (2009), and recognizing the need to update them, particularly in terms of technological advances and characterization, in order to promote more efficient regulatory frameworks from a public health

1 Acknowledging that national authorities may use different terminologies when referring to similar biotherapeutic products. 2 See Annex 6 for the financial and administrative implications for the Secretariat of this resolution. 3 Document A67/32.

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WHA Resolutions perspective that ensure the efficacy, quality and safety of these products at the national and regional levels; Conscious that similar biotherapeutic products could be more affordable and offer better access to treatments of biological origin, while ensuring quality, safety and efficacy, 1. URGES Member States:4 (1) to develop or strengthen, as appropriate, national regulatory assessment and authorization frameworks, with a view to meeting the public health needs for biotherapeutic products, including similar biotherapeutic products; (2) to develop the necessary scientific expertise to facilitate development of solid, scientifically-based regulatory frameworks that promote access to products that are affordable, safe, efficacious and of quality, taking note of the relevant WHO guidelines that may be adapted to the national context and capacity; (3) to work to ensure that the introduction of new national regulations, where appropriate, does not constitute a barrier to access to quality, safe, efficacious and affordable biotherapeutic products, including similar biotherapeutic products; 2. REQUESTS the Director-General: (1) to support Member States in strengthening their capacity in the area of the health regulation of biotherapeutic products, including similar biotherapeutic products; (2) to support, as appropriate, the development of national regulatory frameworks that promote access to quality, safe, efficacious and affordable biotherapeutic products, including similar biotherapeutic products; (3) to encourage and promote cooperation and exchange of information, as appropriate, among Member States in relation to biotherapeutic products, including similar biotherapeutic products; (4) to convene WHO’s Expert Committee on Biological Standardization to update the 2009 guidelines, taking into account the technological advances for the characterization of biotherapeutic products and considering national regulatory needs and capacities and to report on the update to the Executive Board; (5) to report to the Sixty-ninth World Health Assembly on progress in the implementation of this resolution. (Ninth plenary meeting, 24 May 2014 – Committee B, fourth report) æ

4 And, where applicable, regional economic integration organizations.

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Consultation documents

To receive draft monographs by email please contact Mrs Wendy Bonny ([email protected]), specifying that you wish to be added to the electronic mailing list.

The International Pharmacopoeia

Misoprostolum Misoprostol

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.602, January 2015). The working document with line numbers is available for comment at www.who. int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

Molecular formula. C22H38O5 Relative molecular mass. 382.5 Graphic formula

Chemical name. Mixture of methyl 7-[(1RS, 2RS, 3RS)-3-hydroxy-2-[(1E, 4RS)-4-hydroxy-4- methyloct-1-enyl]-5-oxocyclopentyl] heptanoate and methyl 7-[(1RS, 2RS, 3RS)-3-hydroxy- 2-[(1E, 4SR)-4-hydroxy-4-methyloct-1-enyl]-5-oxocyclopentyl] heptanoate; CAS Reg. No. 59122-46-2. Description. Clear, colourless or yellowish, oily liquid. Solubility. Practically insoluble in water R, soluble in dehydrated ethanol R, sparingly soluble in acetonitrile R. Category. Prostaglandin (PGE) analogue. Storage. Misoprostol neat oil should be kept in a tightly sealed container and stored at a temperature between -25 and -10°C. Additional information. Misoprostol is hygroscopic. It is gradually degraded at room temperature, the degradation being faster at higher temperatures.

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Requirements

Definition. Misoprostol contains not less than 96.0% and not more than 102.0% of C22H38O5 with reference to the anhydrous substance. Identity tests Either test A or tests B and C may be applied. A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from misoprostol RS or with the reference spectrum of misoprostol. B. Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R3 as the coating substance and a mixture of 8 volumes of toluene R, 2 volumes of ethyl acetate R, 1 volume of dehydrated ethanol R and 0.1 volume of glacial acetic acid R as the mobile phase, prepared immediately before use. Apply separately to the plate 100 μL of each of the following two solutions in dehydrated ethanol R. For solution (1) use 0.1 mg of the test substance per mL. For solution (2) use 0.1 mg of misoprostol RS per mL. After removing the plate from the chromatographic chamber allow it to dry in air, expose it to the vapour of iodine R and examine the chromatogram in daylight. The principal spot obtained with solution (1) corresponds in position, appearance and intensity to that obtained with solution (2). C. See the test described under “Assay”. The retention time of the principal peak in the chromatogram obtained from solution (1) is similar to that in the chromatogram obtained from solution (2). Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, method A, using 1.0 mL of a 10 mg per mL solution of the test substance in methanol R; the water content is not more than 10 mg/g. Related substances Prepare fresh solutions and perform the tests without delay. Carry out the test as described under 1.14.4 High performance liquid chromatography using a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel (5 μm).1 Use the following conditions for gradient elution: mobile phase A: mix 28 volumes of acetonitrile R with 69 volumes of water R and 3 volumes of methanol R; mobile phase B: mix 47 volumes of acetonitrile R with 50 volumes of water R and 3 volumes of methanol R. Time (min) Mobile phase A Mobile phase B Comment (% v/v) (% v/v) 0–5 100 0 equilibration 5–15 100 to 65 0 to 35 linear gradient 15–22 65 35 isocratic 22–25 65 to 0 35 to 100 linear gradient 25–30 0 100 isocratic 30–32 0 to 100 100 to 0 linear gradient 32–35 100 0 re-equilibration

1 An Ascentis Express C18 column was found suitable.

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Maintain the column temperature at 35°C. Prepare the following solutions using a mixture of 31 volumes of acetonitrile R and 69 volumes of water R as solvent. For solution (1) dissolve 50 mg of the test substance in 10 mL and sonicate for about 10 minutes. Ensure that the temperature of the sonication bath is below room temperature to avoid degradation of misoprostol. For solution (2) dilute a suitable volume of solution (1) to obtain a concentration equivalent to 10 μg of misoprostol per mL. For solution (3) heat 5 mL of solution (1) in a water bath at 75°C for 1 hour. Operate with a flow rate of 1.5 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 200 nm. Store the samples at 4°C during analysis using a cooled autosampler. Inject 20 µL of solution (3). The test is not valid unless the peak-to-valley ratio (Hp/Hv) is at least 5.0, where Hp is the height above the extrapolated baseline of the peak due to impurity A (with a relative retention of about 0.95 with reference to misoprostol (retention time about 21 minutes)) and Hv is the height above the extrapolated baseline at the lowest point of the curve separating the peak due to impurity A from the peak due to misoprostol. Inject alternately 20 μL each of solutions (1) and (2). In the chromatogram obtained with solution (1) the sum of the areas of peaks eluting with a relative retention between 0.80 and 0.98 with reference to misoprostol is not greater than 7.5 times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%). The area of any other impurity peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2%). The sum of the areas of all peaks, other than the principal peak, is not greater than 10 times the area of the principal peak in the chromatogram obtained with solution (2) (2.0%). Disregard any peak with an area less than 0.25 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%). Diastereoisomers Carry out the test as described under 1.14.4 High performance liquid chromatography using a stainless steel column (15 cm × 2.1 mm) packed with silica gel for chromatography R (3.5 μm).2 As the mobile phase use a mixture of 4 volumes of 2-propanol R, 96 volumes of heptane R and 0.1 volume of trifluoroacetic acid R. As the test solution use 1.0 mg of the test substance per mL of a mixture of 4 volumes of 2-propanol R and 96 volumes of heptane R. Maintain the column temperature at 25°C. Operate with a flow rate of 0.5 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 205 nm. Store the samples at 4°C during analysis using a cooled autosampler. Inject 10 µL of the test solution. The chromatogram shows two principal peaks due to misoprostol at retention times of about 14 and 16 minutes. The test is not valid unless the resolution between these two peaks is at least 2.0. Measure the areas of the two peaks corresponding to misoprostol. The first peak of misoprostol is 45% –55% of the sum of the areas of the two peaks due to misoprostol.

2 An Xbridge HILIC column was found suitable.

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Assay Carry out the test as described under 1.14.4 High performance liquid chromatography using a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel (5 μm)3. As the mobile phase use a mixture of 45 volumes of acetonitrile R and 55 volumes of water. Prepare the following solutions in the mobile phase. For solution (1) use 0.1 mg of misoprostol per mL. For solution (2) use 0.1 mg of misoprostol RS per mL. Maintain the column temperature at 35°C. Operate with a flow rate of 1.5 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of about 200 nm. Store the samples at 4°C during analysis using a cooled autosampler. Inject alternately 20 μL each of solutions (1) and (2). The test is not valid unless the symmetry factor of the peak due to misoprostol is between 0.8 and 1.5. Measure the areas of the peak responses obtained in the chromatograms from solutions (1) and (2) and calculate the percentage content of C22H38O5 with reference to the anhydrous substance.

Impurities

its epimer at C* and their enantiomers A. [chemical name to be added] (8-epimisoprostol)

and enantiomer D. [chemical name to be added] (misoprostol B)

its epimer at C* and their enantiomers C. [chemical name to be added] (misoprostol A) ***

3 An Ascentis Express C18 column was found suitable.

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Clindamycini hydrochloridum Clindamycin hydrochloride

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.603, January 2015). The working document with line numbers is available for comment at www.who. int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

C18H33ClN2O5S, HCl Relative molecular mass. 461.5 Chemical name Methyl 7-chloro-6,7,8-trideoxy-6-[[[(2S,4R)-1-methyl-4-propyl-2-pyrrolidinyl]carbonyl]amino]-l- thio-L-threo-α-D-galacto-octopyranoside hydrochloride; CAS Reg.No.21462-39-5. Description. A white or almost white, crystalline powder. Solubility. Very soluble in water, freely soluble in methanol R, and slightly soluble in ethanol (~750 g/L) TS. Category. Antibacterial. Storage. Clindamycin hydrochloride should be kept in a tightly closed container.

Requirements Definition. Clindamycin hydrochloride contains not less than 91.0% and not more than 102.0% of C18H33ClN2O5S, HCl, calculated with reference to the anhydrous substance. Identity test • Either tests A and E or B, D and E or C, D and E may be applied. A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from clindamycin hydrochloride RS or with the reference spectrum of clindamycin hydrochloride. B. Carry out the test as described under 1.14.1. Thin layer chromatography using silica gel R1 as the coating substance and the upper layer of a mixture of 19 volumes of 2-propanol R, 38 volumes of a solution of ammonium acetate (~150 g/L) TS adjusted to pH 9.6 with ammonia (~260 g/L) TS and 43 volumes of ethyl acetate R as the mobile phase. Apply separately to the plate 5 μL of each of the following three solutions in methanol R. For solution (A) use 1 mg of test substance per mL. For solution (B) use 1 mg of Clindamycin hydrochloride RS per mL. For solution (C) use 1 mg of Clindamycin hydrochloride

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RS and 1 mg of lincomycin hydrochloride RS per mL. After removing the plate from the chromatographic chamber dry the plate in air and spray with potassium permanganate (~1 g/L) TS. Examine the chromatogram in daylight. The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B). The test is not valid unless the chromatogram obtained with solution (C) shows 2 clearly separated spots. C. See the test described under “Assay”. The principal peak in the chromatogram obtained with solution (1) is similar in retention time to the principal peak in the chromatogram obtained with solution (2). D. Dissolve about 10 mg in 2 mL of hydrochloric acid (~200 g/L) TS and heat on a water-bath for 3 minutes. Add 3 mL of sodium carbonate (106 g/L) TS and 1 mL of sodium nitroprusside (20 g/L) TS. A violet-red colour develops. E. A 0.01 g/mL solution yields reaction A described under 2.1 General identification tests as characteristic of chlorides. Specific optical rotation. Use a 40.0 mg/mL solution and calculate with reference to the anhydrous substance: = +135° to +150°. Sulfated ash. Not more than 5.0 mg/g. Water. Determine as described under 2.8 Determination of water by Karl Fischer Method, Method A, using 0.5 g of the substance. The water content is not less than 30 mg/g and not more than 60 mg/g. pH value. pH of a 100 mg/mL solution in carbon-dioxide-free water R, 3.0–5.0. Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given below under “Assay”. Prepare the following solutions in the mobile phase. For solution (1) dissolve 100 mg of the test substance and dilute to 25.0 mL. For solution (2) dilute 2.0 mL of solution (1) to 100.0 mL. For solution (3) dissolve 100 mg of clindamycin hydrochloride RS in a 25 mL volumetric flask. Inject alternately 20 μL each of solution (1), (2) and (3). Record the chromatograms for about 2 times the retention time of clindamycin (retention time about 10 minutes). In the chromatogram obtained with solution (3) the peaks are eluted at the following relative retention with reference to clindamycin (retention time about 10 minutes): impurity A (lincomycin) about 0.4; impurity B (clindamycin B) about 0.65; impurity C (7-epiclindamycin) about 0.8. The test is not valid unless the resolutions between the peaks due to impurities B and C and impurity C and clindamycin are at least 3.0. In the chromatogram obtained with solution (1): • the area of any peak corresponding to either impurity B or impurity C is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (2.0%); • the area of any other peak, other than the principal peak, is not greater than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (1.0%); • the sum of the areas of all peaks, other than the principal peak, is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (6.0%). Disregard any peak with an area less than 0.025 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%). Assay. Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 μm).1 As the mobile

1 Hypersil BDS 5 µm was found to be suitable.

51 Consultation documents WHO Drug Information Vol. 29, No. 1, 2015 phase use a mixture of 45 volumes of acetonitrile R and 55 volumes of potassium dihydrogen phosphate (6.8 g/L) TS adjusted to pH 7.5 with potassium hydroxide (~400 g/L) TS. Prepare the following solutions in mobile phase. For solution (1) use a solution containing 1.0 mg of the test substance per mL. For solution (2) use a solution containing 1.0 mg of clindamycin hydrochloride RS per mL. Operate with a flow rate of 1.0 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 210 nm. Inject alternately 20 μL each of solutions (1) and (2). Measure the areas of the peaks corresponding to clindamycin obtained in the chromatograms from solution (1) and (2) and calculate the percentage content of clindamycin hydrochloride

(C18H33ClN2O5S, HCl) using the declared content of C18H33ClN2O5S, HCl in clindamycin hydrochloride RS. Impurities

A. R1=CH2-CH2-CH3, R2=OH, R3=H: methyl 6,8-dideoxy-6-[[[(2S,4R)- 1-methyl-4- propylpyrrolidin-2-yl]carbonyl]amino]-1-thio-d-erythro-α-d-galacto-octopyranoside (lincomycin) B. R1=C2H5, R2=H, R3=Cl: methyl 7-chloro-6,7,8-trideoxy-6-[[[(2S,4R)- 4-ethyl-1- methylpyrrolidin-2-yl]carbonyl]amino]-1-thio-l-threo-α-d-galacto-octopyranoside (clindamycin B) C. R1=CH2-CH2-CH3, R2=Cl, R3=H: methyl 7-chloro-6,7,8-trideoxy-6- [[[(2S,4R)-1-methyl- 4-propylpyrrolidin-2-yl]carbonyl]amino]-1-thio-d-erythro-α-d-galacto-octopyranoside (7-epiclindamycin)

Reagents to be established Hydrochloric acid (~200 g/L) TS Procedure. Dilute hydrochloric acid (~250 g/L) TS with water to contain approximately 200 g of HCl in 1000 mL (approximately 5.5 mol/L). Sodium carbonate (106 g/L) TS

A solution of sodium carbonate R containing about 106 g of Na2CO3 per litre (approximately 1 mol/L). Sodium nitroprusside (20 g/L) TS

A solution of sodium nitroprusside R containing about 20 g of Na2Fe(NO)(CN)5 per litre. Note: Sodium nitroprusside (20 g/L) TS must be freshly prepared. Potassium dihydrogen phosphate (6.8 g/L) TS

A solution of potassium dihydrogen phosphate R containing 6.8 g of KH2PO4 per litre (0.1 mol/L). ***

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Clindamycini hydrochloridi capsulae Clindamycin hydrochloride capsules

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.604, January 2015). The working document with line numbers is available for comment at www.who. int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, CH-1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

Category. Antibacterial. Storage. Clindamycin hydrochloride capsules should be kept in a tightly closed container. Additional information. Strength in the current WHO Model list of essential medicines (EML): 150 mg (as hydrochloride). Strengths in the current EML for Children: 150 mg (as hydrochloride). Labelling. The designation on the container should state the quantity of clindamycin hydrochloride in terms of the equivalent amount of clindamycin. 150 mg of clindamycin is approximately equivalent to 162.9 mg of clindamycin hydrochloride.

Requirements Comply with the monograph for Capsules. Definition. Clindamycin hydrochloride capsules contain clindamycin hydrochloride. They contain not less than 90.0% and not more than 110.0% of the amount of C18H33ClN2O5S stated on the label. Identity tests • Either tests A and D or B and D or C and D may be applied. A. Shake a quantity of the contents of the capsules containing the equivalent of 30 mg of clindamycin with 15 mL of dichlormethane R, filter and evaporate the filtrate to dryness. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from clindamycin hydrochloride RS, treated in the same way as the test substance, or with the reference spectrum of clindamycin hydrochloride. B. Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R1 as the coating substance and the upper layer of a mixture of 19 volumes of 2-propanol R, 38 volumes of a solution of ammonium acetate (~150 g/L) TS adjusted to pH 9.6 with ammonia (~260 g/L) TS and 43 volumes of ethyl acetate R as the mobile phase. Apply separately to the plate 5 μL of each of the following three solutions. For solution (A) shake a quantity of the contents of the capsules equivalent to 10 mg of Clindamycin with 10 mL of methanol R, filter and use the clear filtrate. For solution (B) use 1 mg of clindamycin hydrochloride RS per mL of methanol R. For solution (C) use 1 mg of clindamycin hydrochloride RS and 1 mg of lincomycin hydrochloride RS per mL of methanol R. After removing the plate from the chromatographic chamber allow it to dry in air and spray with potassium permanganate (~1 g/L) TS. Examine the chromatogram in daylight.

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The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B). The test is not valid unless the chromatogram obtained with solution (C) shows two clearly separated spots. D. See the method described under “Assay”. The retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that in the chromatogram obtained with solution (2). E. Shake a quantity of the contents of the capsules containing 50 mg of Clindamycin with 5 mL of water and filter. The clear filtrate yields the reactions described under2.1 General identification tests as characteristic of chlorides. Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, method A, using a quantity of the contents of the capsules equivalent to 0.5 g of Clindamycin; the water content is not more than 70 mg/g. Dissolution/Disintegration Either test A or test B may be applied. A. Dissolution. Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms using as the dissolution medium 900 mL of water and rotating the paddle at 50 revolutions per minute. At 30 minutes withdraw a sample of 15 mL of the medium from each vessel and filter, discarding the first 10 mL of the filtrate. Prepare standard solution as follows: dissolve a suitable amount of clindamycin hydrochloride RS, then add a suitable volume of the dissolution medium to obtain a concentration of 167 µg per mL. Determine

the content of clindamycin (C18H33ClN2O5S) in the filtrate according to the method below. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the chromatographic conditions as described under “Assay”.

For each of the capsules tested calculate the amount of clindamycin (C18H33ClN2O5S) in the

medium using the declared content of C18H33ClN2O5S,HCl in clindamycin hydrochloride RS. Evaluate the results as described under 5.5 Dissolution test for solid oral dosage forms, Acceptance criteria. The amount in solution for each capsule is not less than 80% (Q) of the amount declared on the label. B. Disintegration. Comply with 5.3 Disintegration test for tablets and capsules operating the apparatus for 15 minutes. If the capsules do not comply carry out test A (Dissolution) above. Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given below under “Assay”. Prepare the following solutions in the mobile phase. For solution (1) transfer a quantity of the contents of the capsules equivalent to about 100 mg of Clindamycin into a 25 mL volumetric flask. Add about 20 mL of mobile phase and sonicate for 10 minutes. Dilute to volume with mobile phase, mix and filter. For solution (2) dilute 2.0 mL of solution (1) to 100.0 mL. For solution (3) dissolve 100 mg of clindamycin hydrochloride RS in a 25 mL volumetric flask. Inject alternately 20 μL each of solutions (1), (2) and (3), Record the chromatograms for 2 times the retention time of clindamycin (retention time about 10 minutes). In the chromatogram obtained with solution (3) the peaks are eluted at the following relative retention with reference to clindamycin (retention time about 10 minutes): impurity A (lincomycin) about 0.4; impurity B (clindamycin B ) about 0.65; impurity C (7-epiclindamycin) about 0.8. The test is not valid unless the resolutions between the peaks due to impurities B and C and impurity C and clindamycin are at least 3.0.

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In the chromatogram obtained with solution (1): • the area of any peak corresponding to either impurity B or impurity C is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (2.0%); • the area of any peak, corresponding to impurity A is not greater than 0.5 times the area of the principal peak in the chromatogram obtained with solution (2) (1.0%). Assay. Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25cm × 4.6mm) packed with particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 μm).1 As the mobile phase use a mixture of 45 volumes of acetonitrile R and 55 volumes of a 6.8 g/L solution of potassium dihydrogen phosphate R adjusted to pH 7.5 with potassium hydroxide (~400 g/L) TS. Prepare the following solutions in mobile phase. For solution (1) weigh and mix the contents of 20 capsules. Transfer a quantity of the mixed contents equivalent to about 100 mg of Clindamycin, accurately weighed, into a 100 mL volumetric flask. Add about 80 mL of the mobile phase, sonicate for 10 minutes, make up to volume with the mobile phase, mix and filter. For solution (2) use a solution containing 1.1 mg of Clindamycin hydrochloride RS per mL. Operate with a flow rate of 1.0 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 210 nm. Inject alternately 20 μL each of solutions (1) and (2). Measure the areas of the peaks corresponding to clindamycin obtained in the chromatograms from solution (1) and (2) and calculate the percentage content of clindamycin (C18H33ClN2O5S) in the capsules using the declared content of C18H33ClN2O5S,HCl in clindamycin hydrochloride

RS. Each mg of C18H33ClN2O5S,HCl is equivalent to 0.9209 mg of C18H33ClN2O5S. Impurities. The impurities limited by the requirements of this monograph are impurity A, B and C listed in the monograph for Clindamycin hydrochloride. ***

1 Hypersil BDS 5 µm is suitable.

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Dextromethorphani hydrobromidum Dextromethorphan hydrobromide

This is a draft proposal for The International Pharmacopoeia (Working document QAS/15.605, January 2015).

The working document with line numbers and tracked changes is available for comment at www.who.int/medicines/areas/quality_safety/quality_assurance/projects/en/. Please address any comments to: World Health Organization, Quality Assurance and Safety: Medicines, Dr Herbert Schmidt, 1211 Geneva 27, Switzerland; fax: +41 22 791 4730; email: [email protected].

[Note from the Secretariat. It is proposed to revise the monograph on Dextromethorphan hydrobromide.]

[Note from the editor. In accordance with WHO editorial policy the text reproduced below does not include tracked changes. Changes from the current monograph are indicated by insert and delete in the working document available at the above-mentioned web address.]

Molecular formula. C18H25NO,HBr,H2O Relative molecular mass. 370.3 Graphic formula.

Chemical name. (+)-3-Methoxy-17-methyl-9α,13α-14α-morphinan hydrobromide monohydrate; (+)-cis- 1,3,4,9,10,10a-hexahydro-6-methoxy-11-methyl-2H-10,4a-iminoethanophenanthrene hydrobromide monohydrate; CAS Reg. No. 6700-34-1 (monohydrate). Description. A white or almost white, crystalline powder. Solubility. Sparingly soluble in water; freely soluble in ethanol (~750 g/l) TS; practically insoluble in ether R. Category. Antitussive. Storage. Dextromethorphan hydrobromide should be kept in a well-closed container.

Requirements Definition. Dextromethorphan hydrobromide contains not less than 98.0% and not more than

101.0% of C18H25NO,HBr, calculated with reference to the anhydrous substance. Identity tests • Either tests A, F and E or tests B, F, G and E may be applied. A. Dry a small quantity of the test substance for 4 hours under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury) over phosphorus pentoxide R and carry out the examination as described under 1.7 Spectrophotometry in the infrared region.

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The infrared absorption spectrum is concordant with the spectrum obtained from dextromethorphan hydrobromide RS similarly prepared or with the reference spectrum of dextromethorphan hydrobromide. B. The absorption spectrum of a 0.10 mg/ml solution in sodium hydroxide (0.1 mol/l) VS, when observed between 230 nm and 350 nm, exhibits a maximum at 280 nm; the absorbance of a 1 cm layer at this wavelength is about 0.59. C. [deleted as part of the proposed revision] D. [deleted as part of the proposed revision] E. To a 5 mg/ml solution add 0.25 ml of nitric acid (~130 g/l) TS; this test yields reaction B described under 2.1 General identification tests as characteristic of bromides. F. Determine the specific optical rotation using a 20 mg/mL solution of the test substance in hydrochloric acid (0.1 mol/L) VS. Calculated with reference to the anhydrous substance; the specific optical rotation is between +28.0° to +30.0°. G. Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R1 as the coating substance and a freshly prepared mixture of 2 volumes of ammonia (~260 g/L) TS, 10 volumes of dichloromethane R, 13 volumes of methanol R, 20 volumes of ethyl acetate R and 55 volumes of toluene R as the mobile phase. Apply separately to the plate 5 μL of each of the following 2 solutions in methanol R containing (A) 2.5 mg of the test substance per mL and (B) 2.5 mg of dextromethorphan hydrobromide RS per mL. Develop the plate for a distance of about 15 cm. After removing the plate from the chromatographic chamber allow it to dry in air or in a current of air, spray it with potassium iodobismuthate/tartaric acid TS and examine the chromatogram in daylight. The principal spot obtained with solution (A) corresponds in position, appearance and intensity to that obtained with solution (B).

Sulfated ash. Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A, using about 0.2 g of the substance; the water content is not less than 35 mg/g and not more than 55 mg/g. pH value. Dissolve 0.4 g in carbon-dioxide-free water R using gentle heat, dilute to 20 ml with the same solvent and measure the pH at 20°C; the value lies between 5.2 and 6.5.

Dimethylaniline. Dissolve 0.5 g in 15 ml of water using gentle heat, cool and add 4 ml of acetic acid (~60 g/l) TS, 1 ml of sodium nitrite (10 g/l) TS and sufficient water to produce 25 ml. Prepare similarly a reference solution containing 5 μg of N,N-dimethylaniline R in 25 ml. The colour produced in the test solution is not more intense than that produced in the reference solution when compared as described under 1.11 Colour of liquids; the dimethylaniline content is not more than 10 μg/g.

Phenolic substances. To 5 mg add 1 drop of hydrochloric acid (~70 g/l) TS, 1 ml of water and 0.2 ml of ferric chloride (50 g/l) TS. Mix, add 0.2 ml of potassium ferricyanide (50 g/l) TS, dilute to 5 ml with water, shake well and allow to stand for 15 minutes; the solution is yellowish brown and shows no greenish or blue colour.

Levomethorphan. Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm × 4.6 mm) packed with particles of

57 Consultation documents WHO Drug Information Vol. 29, No. 1, 2015 silica gel, the surface of which has been modified with chemically-bonded cellulose tris(4- methybenzoate) groups (5 μm). As the mobile phase use a mixture of 940 volumes of n-hexane R, 60 volumes of 2-propanol R and 1 volume of diethylamine R. Operate with a flow rate of 0.5 mL per minute. As a detector use an ultraviolet spectrophotometer set at a wavelength of 285 nm. Maintain the column at 30°C. Prepare the following solutions. For solution (1) transfer about 120 mg of the test substance in a 10.0 mL flask. Add 4 mL 2-propanol R, sonicate for about 5 minutes, allow to cool at room temperature and make up to volume with mobile phase. For solution (2) dilute 5.0 mL of solution (1) to 100.0 mL with mobile phase. Dilute 2.0 mL of this solution to 100.0 mL with mobile phase. Prepare solution (3) as indicated in the leaflet of dextromethorphan for system suitability RS (containing a mixture of dextromethorphan and levomethorphan). Inject 20 µL of solution (3). The test is not valid unless the resolution factor between the two principal peaks due to levomethorphan (retention time about 9 minutes) and due to dextromethorphan (retention time of about 12 minutes) is at least 3. Inject alternately 20 µL each of solutions (1) and (2). In the chromatogram obtained with solution (1) the area of any peak corresponding to levomethorphan is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.1 %).

Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm × 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 µm). As the mobile phase use a solution prepared as follows: dissolve 3.11 g of docusate sodium R in a mixture of 400 mL of water R and 600 mL of acetonitrile R, add 0.56 g of ammonium nitrate R and adjust to apparent pH 2.0 with glacial acid R. Operate with a flow of 1.0 mL/min. As a detector use an ultraviolet spectrophotometer set at a wavelength of 280 nm. Prepare the following solutions in mobile phase. For solution (1) use a solution containing 1.0 mg of the test substance per mL. For solution (2) dilute 1.0 mL of solution (1) to 200.0 mL. For solution (3) dissolve 2 mg of dextromethorphan impurity A RS in 2 mL of solution (1) and dilute to 25.0 mL. Inject 20 µL of solution (3). The test is not valid unless the resolution between the peaks due to dextromethorphan (retention time about 22 min) and impurity A (with a relative retention of about 1.1) is at least 1.5. Inject alternately 20 µL each of solutions (1) and (2). Record the chromatograms for about twice the retention time of dextromethorphan. In the chromatogram obtained with solution (1) the following impurities, if present, are eluted at the following relative retention with reference to dextromethorphan (retention time about 22 minutes): impurity B about 0.4; impurity C about 0.8; impurity D about 0.9; and impurity A about 1.1. In the chromatogram obtained with solution (1): • the area of any peak corresponding to either impurity A, impurity B or impurity D is not greater than the area of the principal peak obtained with solution (2) (0.5 %);

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• the area of any peak corresponding to impurity C, when multiplied by a correction factor of 0.2, is not greater than the area of the principal peak obtained with solution (2) (0.5%); • the area or the corrected area of not more than one peak corresponding to either impurity A, impurity B, impurity C or impurity D is greater than 0.5 times the area of the principal peak obtained with solution (2) (0.25 %); • the area of any other peak, other than the principal peak, is not greater than 0.2 times the area of the principal peak obtained with solution (2) (0.10 %); • the sum of the corrected area of any peak corresponding to impurity C and the areas of all other peaks, other than the principal peak, is not greater than twice the area of the principal peak obtained with the solution (2) (1.0 %). Disregard any peak with an area less than 0.1 times the area of the principal peak obtained with solution (2) (0.05%).

Assay Dissolve about 0.3 g, accurately weighed, in a mixture of 5.0 mL of hydrochloric acid (0.1 mol/L) VS and 20 mL of dehydrated ethanol R. Titrate with sodium hydroxide (0.1 mol/L) VS, determining the end-point potentiometrically. Read the volume added between the 2 points of inflexion. Each mL of sodium hydroxide (0.1 mol/L) VS is equivalent to 35.23 mg of

C18H25NO,HBr.

Impurities

A. ent-3-methoxymorphinan,

B. ent-17-methylmorphinan-3-ol,

C. ent-3-methoxy-17-methylmorphinan-10-one,

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D. ent-(14S)-3-methoxy-17-methylmorphinan.

Reagents to be established Potassium iodobismuthate/tartaric acid TS Stock solution. Suspend 1.7 g of bismuth subnitrate R and 20 g of tartaric acid R in 40 mL of water R. To the suspension add 40 mL of potassium iodide (400 g/L) TS and stir for 1 hour. Filter. The solution may be kept for several days in brown bottles. Spray solution. Mix immediately before use 5 mL of the stock solution with 15 mL of water R. Docusate sodium R Sodium 1,4-bis[(2-ethylhexyl)oxy]-1,4-dioxobutane-2-sulfonate. A commercially available reagent of suitable grade. ***

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